Dihydropyrimidin-2-one compounds and medical use thereof

ABSTRACT

A compound of Formula [I] or a pharmaceutically acceptable salt thereof:wherein each symbol is defined as in the specification.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.17/447,805, filed Sep. 15, 2021, which is a continuation of U.S.application Ser. No. 16/902,935, filed Jun. 16, 2020, which is acontinuation of U.S. application Ser. No. 16/228,448, filed Dec. 20,2018, which is a continuation application of U.S. application Ser. No.14/966,120, filed on Dec. 11, 2015, now U.S. Pat. No. 10,196,363, whichclaims the benefit of Japanese Application No. 2014-251771, filed Dec.12, 2014.

TECHNICAL FIELD

The present invention relates to dihydropyrimidin-2-one compounds orpharmaceutically acceptable salts thereof which have inhibitory actionsagainst Retinoid-related Orphan Receptor gamma (RORγ), pharmaceuticalcompositions comprising the same, and medical uses thereof.

BACKGROUND ART

RORγ is a nuclear receptor which is important for the differentiationand activation of Th17 cells. RORγt is also known as a splice variant ofRORγ (Non patent literature 1). RORγ and RORγt differ only in theirN-terminal domains, and share the same ligand-binding domain andDNA-binding domain. It is reported that RORγ is expressed in othertissues besides Th17 cells (Nonpatent literature 1).

By inhibiting RORγ, the differentiation and activation of Th17 cells canbe inhibited. IL-17 produced in Th17 cells is involved in the inductionof a variety of chemokines, cytokines, metalloproteases and otherinflammatory mediators, and the migration of neutrophil, hence, theinhibition of IL-17 may lead to the inhibition of such induction andmigration (Nonpatent literatures 2 and 3).

RORγ in adipose tissues is related to the regulation of adipogenesis,and by inhibiting RORγ, insulin resistance can be improved (Nonpatentliterature 4).

It is known that Th17 cells are involved in autoimmune diseases such asrheumatoid arthritis, psoriasis, inflammatory bowel disease such asCrohn's disease and ulcerative colitis, multiple sclerosis, systemiclupus erythematosus, ankylosing spondylitis, uveitis, polymyalgiarheumatica, type I diabetes, and graft versus host disease; allergicdiseases; dry eye; and fibrosis such as pulmonary fibrosis and primarybiliary cirrhosis. It is known that adipose tissues are involved inmetabolic diseases.

As for rheumatoid arthritis, for example, it is reported that theadministration of anti-IL-17 antibody can improve swelling and jointdestruction associated with collagen-induced arthritis (Nonpatentliterature 5). Moreover, it is reported that swelling and jointdestruction associated with collagen-induced arthritis can be improvedin experiments using IL-17-deficient mice (Nonpatent literature 6).

As for psoriasis, it is reported that in a clinical trial, theadministration of anti-IL-17 antibody is effective in treating psoriasis(Nonpatent literature 7). Anti IL-17 antibodies have been placed on themarket for use in psoriasis (Nonpatent literature 8).

As for inflammatory bowel diseases such as Crohn's disease andulcerative colitis, in a colitis model induced by the adaptive transferof T-cells, the adaptive transfer of T-cells derived from RORγ-KO micedoes not increase IL-17 in the mucosa, thereby the onset of colitis canbe suppressed (Nonpatent literature 9).

As for multiple sclerosis, the disease state of mouse experimentalautoimmune encephalomyelitis model which is an animal model of multiplesclerosis can be suppressed in RORγt-KO mice (Nonpatent literature 10).

As for systemic lupus erythematosus, it is reported that the onset ofGBM nephritis model which is an animal model of glomerulonephritis canbe inhibited in RORγt-KO mice (Nonpatent literature 11). Nephritisassociated with SLE may also be suppressed (Nonpatent literature 12).

As for ankylosing spondylitis, it is reported that the administration ofanti-IL-17 antibody is effective in treating ankylosing spondylitis(Nonpatent literature 13).

As for uveitis, it is reported that the administration of anti-IL-17antibody is effective in treating uveitis associated with Behcet'sdisease, sarcoidosis and Harada disease (Nonpatent literature 7).

As for polymyalgia rheumatica, an efficacy of anti-IL-17 antibody intreatment of polymyalgia rheumatica is currently tested in a clinicaltrial.

As for type I diabetes, the disease state of NOD mice which is a type Idiabetes model can be suppressed by the administration of anti-IL-17antibody (Nonpatent literature 14).

As for graft versus host disease, it is reported in a mouse transplantmodel that a survival rate and a rejection in a host would be improvedby transfecting RORγKO mouse-derived cells (Nonpatent literature 19).

As for allergic disease such as asthma, in OVA-sensitized model, theattenuated eosinophilic pulmonary inflammation, the reduced numbers ofCD4+ lymphocytes, and the decrease of Th2 cytokines/chemokines level areexhibited in RORγ-KO mice, that is, the allergenic reaction can beinhibited in RORγ-KO mice (Nonpatent literature 15).

As for dry eye, it is reported that the Th17 cells increases in ananimal model of dry eye, and an efficacy of anti-IL-17 antibody in dryeye patient is currently tested in a clinical trial (Nonpatentliterature 16).

As for fibrosis, in a bleomycin-induced pulmonary fibrosis model whichis an animal model of pulmonary fibrosis, the administration ofanti-IL-17 antibody can inhibit inflammation and fibrosis in lung andcan increase survival of the animal (Nonpatent literature 17).

As for primary biliary cirrhosis, it is reported that Th17 cells in thelesion area of a patient with a primary biliary cirrhosis increase, andan efficacy of an antibody to IL-23 which activates Th17 cells iscurrently tested in a clinical trial (Nonpatent literature 18).

As for metabolic disease, the insulin resistance which is induced byfeeding a high-fat diet can be suppressed in RORγ KO mice (Nonpatentliterature 4).

On the basis of these findings, RORγ antagonists are thought to beuseful for preventing or treating autoimmune disease such as rheumatoidarthritis, psoriasis, inflammatory bowel disease such as Crohn's diseaseand ulcerative colitis, multiple sclerosis, systemic lupuserythematosus, ankylosing spondylitis, uveitis, polymyalgia rheumatica,type I diabetes, and graft versus host disease; allergic diseases suchas asthma; dry eye; fibrosis such as pulmonary fibrosis and primarybiliary cirrhosis; and metabolic diseases such as diabetes.

LIST OF NONPATENT LITERATURES

[Nonpatent literature 1]  Anton. 2009 NRS 7, 1-32 [Nonpatent literature2]  Koenders et al. 2006 Ann Rheum Dis 65 (Suppl III), iii29-iii33[Nonpatent literature 3]  Carsten et al. 2007 J Allergy Clin Immunol120, 247-54 [Nonpatent literature 4]  Bettina et al. 2011 EMBO Mol Med3, 1-15 [Nonpatent literature 5]  Hilde et al. 2009 Arthritis Research &Therapy 11: R122 [Nonpatent literature 6]  Susumu et al. 2003 J. Immnol171, 6173-6177 [Nonpatent literature 7]  Wolfgang et al. 2010 Sci TranslMed 2, 52ra72 [Nonpatent literature 8]  Sanford et al. Drugs (2015) 75:329-338 [Nonpatent literature 9]  Moritz et al. 2009 Gastroenterology136, 257-67 [Nonpatent literature 10] Ivaylo et al. 2006 Cell 126,1121-1133 [Nonpatent literature 11] Oliver et al. 2011 J Am Soc Nephrol22: 472-483 [Nonpatent literature 12] Jose et al. 2010 Curr OpinRheumatol 22, 499-503 [Nonpatent literature 13] Dominique et al. Lancet2013, 382(9906): 1705 [Nonpatent literature 14] Juliet et al. 2009Diabetes 58: 1302-1311 [Nonpatent literature 15] Stephen et al. 2007 J.Immnol 178, 3208-18 [Nonpatent literature 16] ClinicalTrials.govIdentifier: NCT01250171 [Nonpatent literature 17] Su et al. 2011 J.Immnol 187 [Nonpatent literature 18] ClinicalTrials.gov Identifier:NCT01389973 [Nonpatent literature 19] Fulton LM et al. 2012 J.Immunol15; 189(4): 1765-1772

SUMMARY OF INVENTION

An object of the present invention is to provide dihydropyrimidin-2-onecompounds or pharmaceutically acceptable salts thereof which haveinhibitory actions against RORγ, pharmaceutical compositions comprisingthe same, and medical uses thereof.

In particular, the present invention relates to compounds which wouldinhibit differentiation and activation of T helper 17 (Th17) cells by aninhibitory action for Retinoid-related Orphan Receptor gamma: RORγ andinhibit interleukin-17 (IL-17) production.

The present invention is also directed to provide an agent forpreventing or treating autoimmune disease such as rheumatoid arthritis,psoriasis, inflammatory bowel disease such as Crohn's disease andulcerative colitis, multiple sclerosis, systemic lupus erythematosus,ankylosing spondylitis, uveitis, polymyalgia rheumatica, type Idiabetes, and graft versus host disease; allergic disease such asasthma; dry eye; fibrosis such as pulmonary fibrosis and primary biliarycirrhosis; and metabolic disease such as diabetes.

The present inventors have found dihydropyrimidin-2-one compounds whichare RORγ antagonists, thereby have completed the present invention.

That is, the present invention includes the following embodiments.

-   -   [01] A compound of Formula [I] or a pharmaceutically acceptable        salt thereof:

-   -   wherein    -   R¹ is    -   (1) C₄₋₈ alkyl,    -   (2) C₃₋₈ alkyl substituted with one hydroxy,    -   (3) C₄₋₈ alkyl substituted with one halogen,    -   (4) C₄₋₈ alkenyl,    -   (5) C₄₋₈ alkenyl,    -   (6) C₃₋₇ alkyl substituted with one trifluoromethyl,    -   (7) C₁₋₅ alkyl substituted with one substituent selected from        Group X^(a1),    -   (8) C₃₋₆ alkoxy,    -   (9) C₂₋₇ alkoxy substituted with one trifluoromethyl,    -   (10) C₁₋₃ alkoxy substituted with one substituent selected from        Group X^(a2),    -   (11) C₄₋₆ cycloalkyl,    -   (12) C₃₋₆ cycloalkyl substituted with the same or different one        to two C₁₋₅ alkyl,    -   (13) C₅₋₆ cycloalkenyl optionally substituted with the same or        different one to two C₁₋₄ alkyl,    -   (14) spiro C₆₋₁₁ cycloalkyl,    -   (15) C₁₋₃ alkoxycarbonyl,    -   (16) C₃₋₆ alkylsulfanyl,    -   (17) C₃₋₆ alkylsulfinyl,    -   (18) C₃₋₆ alkylsulfonyl,    -   (19) C₃₋₆ cycloalkylsulfanyl,    -   (20) C₃₋₆ cycloalkylsulfinyl,    -   (21) C₃₋₆ cycloalkylsulfonyl,    -   (22) cyclobutylidenemethyl,    -   (23) cyclopentylidenemethyl,    -   (24) cyclohexylidenemethyl optionally substituted with the same        or different one to two C₁₋₃ alkyl,    -   (25) tetrahydropyran-4-ylidenemethyl,    -   (26) C₃₋₆ cycloalkyl substituted with one to the same two        halogen, or    -   (27) C₅₋₆ cycloalkenyl substituted with one to the same two        halogen;    -   Group X^(a1) is    -   (a) C₃₋₆ cycloalkyl optionally substituted with the same or        different one to three C₁₋₅ alkyl,    -   (b) C₃₋₆ cycloalkyl substituted with the same or different one        to two halogen,    -   (c) phenyl,    -   (d) C₂₋₄ alkoxy,    -   (e) trimethylsilyl,    -   (f) carboxy, and    -   (g) tetrahydropyran-4-yl;    -   Group X^(a2) is    -   (a) C₃₋₆ cycloalkyl,    -   (b) phenyl, and    -   (c) C₁₋₄ alkoxy;    -   R² is    -   (1) halogen,    -   (2) C₁₋₆ alkyl,    -   (3) C₁₋₃ alkoxy optionally substituted with phenyl, or    -   (4) trifluoromethyl;    -   n is an integer of 0, 1 or 2, provided that when n is 2, each R²        may be different with each other; or    -   R¹ and R² may combine together with the benzene ring to which        they attach to form indanyl where the indanyl may be substituted        with the same or different one to two C₁₋₆ alkyl;    -   R³ is    -   (1) —Y^(b)—COO—R³⁰,    -   (2) C₁₋₆ alkyl optionally substituted with one hydroxy,    -   (3) C₁₋₆ alkyl substituted with one C₁₋₄ alkoxy,    -   (4) C₁₋₆ alkyl substituted with one C₁₋₄ alkylsulfonyl,    -   (5) C₃₋₆ cycloalkyl optionally substituted with the same or        different one to three substituent(s) selected from Group X^(b),    -   (6)

-   -   (7)

-   -   (8) phenyl,    -   (9)

-   -   (10) C₂₋₃ alkenyl;    -   Y^(b) is    -   (a) C₁₋₆ alkylene,    -   (b) C₃₋₆ cycloalkylene,    -   (c) phenylene,    -   (d) pyridinediyl or    -   (e)

-   -   R³⁰ is    -   (a) hydrogen or (b) C₁₋₄ alkyl;    -   Group X^(b) is    -   (a) halogen,    -   (b) C₁₋₆ alkyl,    -   (c) C₁₋₃ alkyl substituted with one hydroxy,    -   (d) C₁₋₃ alkyl substituted with one C₁₋₃ alkoxy, and    -   (e) C₁₋₃ alkoxy;    -   R⁴ is    -   (1) hydrogen or (2) methyl;    -   R⁵ is    -   (1) —Y^(c)—COO—R⁵⁰,    -   (2) hydrogen,    -   (3) C₁₋₄ alkyl optionally substituted with one C₁₋₃ alkoxy,    -   (4) C₁₋₄ alkyl substituted with one amide,    -   (5) C₁₋₃ alkyl substituted with one C₃₋₆ cycloalkyl substituted        with the same or different two halogen,    -   (6) C₃₋₆ cycloalkyl optionally substituted with one hydroxy-C₁₋₄        alkyl,    -   (7) C₃₋₆ cycloalkyl substituted with one C₁₋₃ alkoxy,    -   (8) C₃₋₆ cycloalkyl substituted with one C₁₋₃ alkoxy-C₁₋₃ alkyl,    -   (9) C₃₋₆ cycloalkyl substituted with the same or different one        to two halogen,    -   (10) C₃₋₆ cycloalkyl substituted with the same or different one        to two C₁₋₃ alkyl,    -   (11) tetrahydropyran-4-yl or    -   (12) pyridin-4-yl;    -   Y^(c) is    -   (a) C₁₋₆ alkylene optionally substituted with one hydroxy,    -   (b) CH₂—CH₂—O—CH₂ or    -   (c) (CH₂)_(m)—Y^(c1)—(CH₂)_(w);    -   m is an integer of 0, 1 or 2;    -   w is an integer of 0, 1 or 2;    -   Y^(c1) is    -   (a) C₃₋₆ cycloalkylene optionally substituted with one C₁₋₃        alkyl,    -   (b) phenylene,    -   (c) phenylene substituted with one halogen,    -   (d) phenylene substituted with one C₁₋₃ alkyl,    -   (e) phenylene substituted with one C₁₋₃ alkoxy,    -   (1) phenylene substituted with one trifluoromethyl,    -   (g) cross-linked C₅₋₈ cycloalkylene,    -   (h)

-   -   (i)

-   -   (j) spiro[3.3]heptanediyl,    -   (k) pyrrolidinediyl,    -   (l) pyrrolidinediyl substituted with one carboxy,    -   (in) pyrrolidinediyl substituted with one C₁₋₃ alkylcarbonyl,    -   (n) pyrrolidinediyl substituted with one C₁₋₃ alkylsulfonyl,    -   (o) pyridinediyl,    -   (p) isoxazolediyl or    -   (q) pyrazolediyl substituted with one C₁₋₃ alkyl;    -   R⁵⁰ is    -   (a) hydrogen or (b) C₁₋₄ alkyl;    -   R⁶ is    -   (1) hydrogen or (2) methyl;    -   provided that when R⁵ is —Y^(c)—COO—R⁵⁰, Y^(c) is        (CH₂)_(m)—Y^(c1)—(CH₂)_(w), m and w are 0, and Y^(c1) is (b)        phenylene, (c) phenylene substituted with one halogen, (d)        phenylene substituted with one C₁₋₃ alkyl, (e) phenylene        substituted with one C₁₋₃ alkoxy or (f) phenylene substituted        with one trifluoromethyl, then R⁶ is methyl; and    -   either R³ or R⁵ or both of them have “—COO—”.    -   [02] The compound of [01], wherein the compound of Formula [I]        is a compound of Formula [II], or a pharmaceutically acceptable        salt thereof:

-   -   wherein    -   R³ is    -   (1) C₁₋₆ alkyl optionally substituted with one hydroxy,    -   (2) C₁₋₆ alkyl substituted with one C₁₋₄ alkoxy,    -   (3) C₁₋₆ alkyl substituted with one C₁₋₄ alkylsulfonyl,    -   (4) C₃₋₆ cycloalkyl optionally substituted with the same or        different one to three substituent(s) selected from Group X^(b),    -   (5)

-   -   (6)

-   -   (7) phenyl,    -   (8)

-   -    or    -   (9) C₂₋₃ alkenyl; and the other symbols have the same meanings        as defined in [01].    -   [03] The compound of [01], wherein the compound of Formula [I]        is a compound of Formula [III], or a pharmaceutically acceptable        salt thereof:

-   -   wherein    -   R⁵ is    -   (1) hydrogen,    -   (2) C₁₋₄ alkyl optionally substituted with one C₁₋₃ alkoxy,    -   (3) C₁₋₄ alkyl substituted with one amide,    -   (4) C₁₋₃ alkyl substituted with one C₃₋₆ cycloalkyl substituted        with the same or different two halogen,    -   (5) C₃₋₆ cycloalkyl optionally substituted with one hydroxy-C₁₋₄        alkyl,    -   (6) C₃₋₆ cycloalkyl substituted with one C₁₋₃ alkoxy,    -   (7) C₃₋₆ cycloalkyl substituted with one C₁₋₃ alkoxy-C₁₋₃ alkyl,    -   (8) C₃₋₆ cycloalkyl substituted with the same or different one        to two halogen,    -   (9) C₃₋₆ cycloalkyl substituted with the same or different one        to two C₁₋₃ alkyl,    -   (10) tetrahydropyran-4-yl or    -   (11) pyridin-4-yl; and the other symbols have the same meanings        as defined in [01].    -   [04] The compound of [01], wherein the compound of Formula [I]        is a compound of Formula [IV], or a pharmaceutically acceptable        salt thereof:

-   -   wherein each symbol has the same meaning as defined in [01].    -   [5] The compound of any one of [01] to [04], wherein R⁶ is        methyl, or a pharmaceutically acceptable salt thereof.    -   [6] The compound of any one of [01] to [05], wherein R⁴ is        hydrogen, or a pharmaceutically acceptable salt thereof.    -   [07] The compound of any one of [01] to [06], wherein n is an        integer of 1 or 2, or a pharmaceutically acceptable salt        thereof.    -   [08] The compound of any one of [01] to [07], wherein R² is        halogen or trifluoromethyl, or a pharmaceutically acceptable        salt thereof.    -   [09] The compound of any one of [01], [02], [04] to [07] or        [08], wherein Y^(c) is    -   (a) C₁₋₆ alkylene or    -   (b) (CH₂)_(m)—Y^(c1)—(CH₂)_(w);    -   m is an integer of 0 or 1;    -   w is an integer of 0 or 1;    -   Y^(c1) is    -   (a) C₃₋₆ cycloalkylene optionally substituted with one        C₁₋₃alkyl,    -   (b) phenylene,    -   (c) phenylene substituted with one halogen,    -   (d) phenylene substituted with one C₁₋₃ alkyl,    -   (e) phenylene substituted with one C₁₋₃ alkoxy,    -   (f) phenylene substituted with one trifluoromethyl,    -   (g) cross-linked C₅₋₈ cycloalkylene,    -   (h) pyridinediyl or    -   (i) pyrazolediyl substituted with one alkyl; and    -   R³ is    -   (1) C₁₋₆ alkyl optionally substituted with one hydroxy,    -   (2) C₁₋₆ alkyl substituted with one C₁₋₄ alkoxy or    -   (3) C₃₋₆ cycloalkyl optionally substituted with the same or        different one to three substituent(s) selected from Group X^(b),        or a pharmaceutically acceptable salt thereof    -   [10] The compound of [02], wherein R⁵⁰ is hydrogen, or a        pharmaceutically acceptable salt thereof.    -   [11] The compound of [01], wherein the compound of Formula [I]        is any one of the compounds of Formulae [IV-B-A] to [IV-B-N], or        a pharmaceutically acceptable salt thereof:

-   -   wherein    -   R^(3h) is hydrogen or methyl;    -   R^(3w) is methyl or fluoro;    -   nX is an integer of 0 or 2;    -   n^(w) is an integer of 0, 1, 2 or 3;    -   R³ is C₁₋₆ alkyl optionally substituted with one hydroxy, C₁₋₆        alkyl substituted with one C₁₋₄ alkoxy or C₃₋₆ cycloalkyl        optionally substituted with the same or different one to three        substituent(s) selected from Group X^(b);    -   R^(5B) is hydrogen, halogen, C₁₋₃ alkyl, C₁₋₃ alkoxy or        trifluoromethyl; and the other symbols have the same meanings as        defined in [01].    -   [12] The compound of [01], selected from the group consisting of        the following formulae, or a pharmaceutically acceptable salt        thereof.

-   -   [13] A pharmaceutical composition comprising the compound of any        one of [01] to [12] or a pharmaceutically acceptable salt        thereof and a pharmaceutically acceptable carrier.    -   [14] An RORγ antagonist comprising the compound of any one of        [01] to [12] or a pharmaceutically acceptable salt thereof and a        pharmaceutically acceptable carrier.    -   [15] An agent for treating or preventing a disease selected from        the group consisting of autoimmune disease, allergic disease,        dry eye, fibrosis, and metabolic disease, comprising the        compound of any one of [01] to [12] or a pharmaceutically        acceptable salt thereof.    -   [16] The agent of [15], wherein the disease is autoimmune        disease.    -   [17] The agent of [16], wherein the autoimmune disease is        selected from the group consisting of rheumatoid arthritis,        psoriasis, inflammatory bowel disease such as Crohn's, disease        and ulcerative colitis, multiple sclerosis, systemic lupus        erythematosus, ankylosing spondylitis, uveitis, polymyalgia        rheumatica, type I diabetes, and graft versus host disease.    -   [18] The agent of [15], wherein the disease is metabolic        disease.    -   [19] The agent of [18], wherein the metabolic disease is        diabetes.    -   [20] A method of inhibiting RORγ, comprising administering to a        mammal a therapeutically effective amount of the compound of any        one of [01] to [12] or a pharmaceutically acceptable salt        thereof.    -   [21] A method of treating or preventing a disease selected from        the group consisting of autoimmune disease, allergic disease,        dry eye, fibrosis, and metabolic disease, comprising        administering to a mammal an effective amount of the compound of        any one of [01] to [12] or a pharmaceutically acceptable salt        thereof.    -   [22] The method of [21], wherein the disease is autoimmune        disease.    -   [23] The method of [22], wherein the autoimmune disease is        selected from the group consisting of rheumatoid arthritis,        psoriasis, inflammatory bowel disease such as Crohn's disease        and ulcerative colitis, multiple sclerosis, systemic lupus        erythematosus, ankylosing spondylitis, uveitis, polymyalgia        rheumatica, type I diabetes, and graft versus host disease.    -   [24] The method of [21], wherein the disease is metabolic        disease.    -   [25] The method of [24], wherein the metabolic disease is        diabetes.    -   [26] Use of the compound of any one of [01] to [12] or a        pharmaceutically acceptable salt thereof for the manufacture of        an RORγ antagonist.    -   [27] Use of the compound of any one of [01] to [12] or a        pharmaceutically acceptable salt thereof for the manufacture of        an agent for treating or preventing a disease selected from the        group consisting of autoimmune disease, allergic disease, dry        eye, fibrosis, and metabolic disease.    -   [28] The use of [27], wherein the disease is autoimmune disease.    -   [29] The use of [28], wherein the autoimmune disease is selected        from the group consisting of rheumatoid arthritis, psoriasis,        inflammatory bowel disease such as Crohn's disease and        ulcerative colitis, multiple sclerosis, systemic lupus        erythematosus, ankylosing spondylitis, uveitis, polymyalgia        rheumatica, type I diabetes, and graft versus host disease.    -   [30] The use of [27], wherein the disease is metabolic disease.    -   [31] The use of [30], wherein the metabolic disease is diabetes.    -   [32] A compound of any one of [01] to [12] or a pharmaceutically        acceptable salt thereof for use as an RORγ antagonist.    -   [33] A compound of any one of [01] to [12] or a pharmaceutically        acceptable salt thereof for use as an agent for treating or        preventing a disease selected from the group consisting of        autoimmune disease, allergic disease, dry eye, fibrosis, and        metabolic disease.    -   [34] The compound of [33], wherein the disease is autoimmune        disease, or a pharmaceutically acceptable salt thereof.    -   [35] The compound of [34], wherein the autoimmune disease is        selected from the group consisting of rheumatoid arthritis,        psoriasis, inflammatory bowel disease such as Crohn's disease        and ulcerative colitis, multiple sclerosis, systemic lupus        erythematosus, ankylosing spondylitis, uveitis, polymyalgia        rheumatica, type I diabetes, and graft versus host disease, or a        pharmaceutically acceptable salt thereof.    -   [36] The compound of [33], wherein the disease is metabolic        disease, or a pharmaceutically acceptable salt thereof.    -   [37] The compound of [36], wherein the metabolic disease is        diabetes, or a pharmaceutically acceptable salt thereof.

Dihydropyrimidin-2-one compounds and pharmaceutically acceptable saltsthereof of the present invention is useful as an agent for prevention ortreatment of autoimmune diseases such as rheumatoid arthritis,psoriasis, inflammatory bowel disease such as Crohn's disease andulcerative colitis, multiple sclerosis, systemic lupus erythematosus,ankylosing spondylitis, uveitis, polymyalgia rheumatica, type Idiabetes, and graft versus host disease, allergic diseases such asasthma, dry eye, fibrosis such as pulmonary fibrosis and primary biliarycirrhosis, and metabolic diseases such as diabetes.

DESCRIPTION OF EMBODIMENTS

Definitions of terms used herein are as follows.

“Halogen” includes fluoro, chloro, bromo or iodo. A preferable “halogen”is fluoro or chloro.

“Alkyl” means a straight or branched chain saturated hydrocarbon group,and includes, for example, “C₁₋₃ alkyl”, “C₁₋₄ alkyl”, “C₁₋₅ alkyl”,“C₁₋₆ alkyl”, “C₄₋₆ alkyl”, “C₄₋₈ alkyl”, and “C₅₋₈ alkyl”, each ofwhich means alkyl with 1 to 3 of carbon atom(s), 1 to 4 of carbonatom(s), 1 to 5 of carbon atom(s), 1 to 6 of carbon atom(s), 4 to 6 ofcarbon atoms, 4 to 8 of carbon atoms, and 5 to 8 of carbon atoms,respectively.

An illustrative example of “C₁₋₃ alkyl” includes, for example, methyl,ethyl, propyl, and isopropyl. A preferable “C₁₋₃ alkyl” is methyl.

An illustrative example of “C₁₋₄ alkyl” includes, for example, methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, and1-methylpropyl. A preferable “C₁₋₄ alkyl” is methyl or ethyl.

An illustrative example of “C₁₋₅ alkyl” includes, for example, methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,1-methylpropyl, pentyl, isopentyl, neopentyl, 1,2-dimethylpropyl, and1-ethylpropyl. A preferable “C₁₋₅ alkyl” is methyl.

An illustrative example of “C₁₋₆ alkyl” includes, for example, methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,1-methylpropyl, pentyl, isopentyl, neopentyl, 1,2-dimethylpropyl,1-ethylpropyl, hexyl, isohexyl, 1,2,2-trimethylpropyl,1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, and2-ethylbutyl. A preferable “C₁₋₆ alkyl” is methyl, ethyl, isopropyl,isobutyl, tert-butyl, isopentyl, neopentyl, 1-methylpropyl or1,1-dimethylbutyl.

An illustrative example of “C₄₋₆ alkyl” includes, for example, butyl,isobutyl, sec-butyl, tert-butyl, 1-methylpropyl, pentyl, isopentyl,neopentyl, 1,2-dimethylpropyl, 1-ethylpropyl, hexyl, isohexyl,1,2,2-trimethylpropyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl,3,3-dimethylbutyl, and 2-ethylbutyl. A preferable one is isobutyl orisopentyl.

An illustrative example of “C₄₋₈ alkyl” includes, for example, butyl,isobutyl, sec-butyl, tert-butyl, 1-methylpropyl, pentyl, isopentyl,neopentyl, 1,2-dimethylpropyl, 1-ethylpropyl, hexyl, isohexyl,1,2,2-trimethylpropyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl,3,3-dimethylbutyl, 2-ethylbutyl, heptyl, 4,4-dimethylpentyl,1-methyl-3,3-dimethylbutyl, octyl, and 2-propylpentyl. A preferable oneis butyl, isobutyl, pentyl, isopentyl, 3,3-dimethylbutyl, 2-ethylbutyl,4,4-dimethylpentyl, 1-methyl-3,3-dimethylbutyl or 2-propylpentyl.

An illustrative example of “C₅₋₈ alkyl” includes, for example, pentyl,isopentyl, neopentyl, 1,2-dimethylpropyl, 1-ethylpropyl, hexyl,isohexyl, 1,2,2-trimethylpropyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl,3,3-dimethylbutyl, 2-ethylbutyl, heptyl, 4,4-dimethylpentyl,1-methyl-3,3-dimethylbutyl, octyl, and 2-propylpentyl. A preferable oneis pentyl, isopentyl, 3,3-dimethylbutyl, 2-ethylbutyl,4,4-dimethylpentyl, 1-methyl-3,3-dimethylbutyl or 2-propylpentyl.

“C₁₋₆ alkyl optionally substituted with one hydroxy” means “C₁₋₆ alkylsubstituted with one hydroxy” or “unsubstituted C₁₋₆ alkyl”.

“C₁₋₃ alkyl substituted with one hydroxy” means “alkyl”, with 1 to 3 ofcarbon atom(s), substituted at any position with one hydroxy. Inparticular, it includes, for example, hydroxymethyl.

“C₅₋₈ alkyl substituted with one hydroxy” means “alkyl”, with 5 to 8 ofcarbon atoms, substituted with at any position with one hydroxy. Inparticular, it includes, for example, 3,3-dimethyl-3-hydroxypropyl,3,3-dimethyl-2-hydroxybutyl, and 3,3-dimethyl-4-hydroxybutyl.

“C₅₋₈ alkyl substituted with one halogen” means “alkyl”, with 5 to 8 ofcarbon atoms, substituted with at any position with one halogen. Inparticular, it includes, for example, 3-fluoro-3-methylbutyl.

“C₃₋₇ alkyl substituted with one trifluoromethyl” means “alkyl”, with 3to 7 of carbon atoms, substituted at any position with onetrifluoromethyl. In particular, it includes, for example,4,4,4-trifluorobutyl and 4,4,4-trifluoro-3,3-dimethylbutyl.

“Alkenyl” means a straight or branched chain unsaturated hydrocarbongroup with one or more double bond(s) between carbon atoms, andincludes, for example, “C₂₋₃ alkenyl” and “C₄₋₈ alkenyl” which “C₂₋₃alkenyl” means alkenyl with 2 to 3 of carbon atoms and “C₄₋₈ alkenyl”means alkenyl with 4 to 8 of carbon atoms. A preferable “C₄₋₈ alkenyl”is “C₄₋₆ alkenyl” with one double bond between carbon atoms.

An illustrative example of “C₂₋₃ alkenyl” includes, for example, ethenyland isopropenyl. A preferable one is isopropenyl.

An illustrative example of “C₄₋₈ alkenyl” includes, for example,2-methyl-prop-1-enyl, 3,3-dimethyl-but-1-enyl, and 3-methyl-but-2-enyl.A preferable one is 2-methyl-prop-1-enyl or 3,3-dimethyl-but-1-enyl.

“Alkynyl” means a straight or branched chain unsaturated hydrocarbongroup with one or more triple bond(s) between carbon atoms, andincludes, for example, “C₄₋₈ alkynyl” which means alkynyl with 4 to 8carbon atoms. A preferable “C₄₋₈ alkynyl” is “C₄₋₆ alkynyl” with onetriple bond between carbon atoms.

An illustrative example of “C₄₋₈ alkynyl” includes, for example,3,3-dimethyl-but-1-ynyl, 3-methyl-but-1-ynyl, and 3-ethyl-pent-1-ynyl. Apreferable one is 3,3-dimethyl-but-1-ynyl.

“Alkoxy” means a group where a straight or branched chain saturatedhydrocarbon group attaches to oxygen atom, and includes, for example.“C₁₋₃ alkoxy”, “C₁₋₄ alkoxy”, “C₂₋₄ alkoxy”, “C₃₋₆ alkoxy”, and “C₂₋₇alkoxy”, each of which means alkoxy with 1 to 3 of carbon atom(s), 1 to4 of carbon atom(s), 2 to 4 of carbon atoms, 3 to 6 of carbon atoms, and2 to 7 of carbon atoms, respectively.

An illustrative example of “C₁₋₃ alkoxy” includes, for example, methoxy,ethoxy, propoxy, and isopropoxy. A preferable one is methoxy or ethoxy.

An illustrative example of “C₁₋₄ alkoxy” includes, for example, methoxy,ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, andtert-butoxy. A preferable one is methoxy.

An illustrative example of “C₂₋₄ alkoxy” includes, for example, ethoxy,propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, and tert-butoxy. Apreferable one is isopropoxy or tert-butoxy.

An illustrative example of “C₃₋₆, alkoxy” includes, for example,propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy,pentyloxy, isopentyloxy, 2-methylbutoxy, 1,1-dimethylpropoxy,neopentyloxy, 3,3-dimethylbutoxy, 1-ethylpropoxy, and hexyloxy. Apreferable one is isobutoxy, isopentyloxy, neopentyloxy or3,3-dimethylbutoxy.

An illustrative example of “C₂₋₇ alkoxy” includes, for example, ethoxy,propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, and tert-butoxy. Apreferable one is isopropoxy or tert-butoxy.

“C₂₋₇ alkoxy substituted with one trifluoromethyl” means “alkoxy”, with2 to 7 carbon atoms, substituted at any position with one“trifluoromethyl”. Its illustrative example includes, for example,3,3,3-trifluoropropoxy, 4,4,4-trifluorobutoxy, 5,5,5-trifluoropentyloxy,6,6,6-trifluorohexyloxy, 7,7,7-trifluoroheptyloxy, and8,8,8-trifluorooctyloxy. A preferable one includes, for example,3,3,3-trifluoropropoxy.

“C₁₋₃ alkyl substituted with one C₁₋₃ alkoxy” means “alkyl”, with 1 to 3of carbon atom(s), substituted at any position with one C₁₋₃ alkoxy. Inparticular, it includes, for example, methoxymethyl.

“C₁₋₆ alkyl substituted with one C₁₋₄ alkoxy” means “alkyl”, with 1 to 6of carbon atom(s), substituted at any position with one C₁₋₄ alkoxy. Inparticular, it includes, for example, 2-methoxyethyl,1-methyl-2-methoxyethyl, 2-methoxypropyl, 4-methoxy-2,2-dimethylbutyl,and 3-tert-butoxypropyl.

“Cycloalkyl” means a monocyclic saturated hydrocarbon group, andincludes, for example, “C₃₋₆ cycloalkyl” and “C₄₋₆ cycloalkyl”, each ofwhich means cycloalkyl with 3 to 6 of carbon atoms, and 4 to 6 of carbonatoms, respectively.

An illustrative example of “C₃₋₆ cycloalkyl” includes, for example,cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

An illustrative example of “C₄₋₆ cycloalkyl” includes, for example,cyclobutyl, cyclopentyl, and cyclohexyl.

“C₃₋₆ cycloalkyl substituted with one C₁₋₃ alkoxy” means “cycloalkyl”,with 3 to 6 of carbon atoms, substituted at any position with one C₁₋₃alkoxy. In particular, it includes, for example, 3-methoxycyclobutyl.

“C₃₋₆ cycloalkyl substituted with one C₁₋₃ alkoxy-C₁₋₃ alkyl” means“cycloalkyl”, with 3 to 6 of carbon atoms, substituted at any positionwith one C₁₋₃ alkoxy-C₁₋₃ alkyl. In particular, it includes, forexample, 1-methoxymethylcyclopropyl and 3-methoxymethylcyclobutyl.

“Cycloalkenyl” means a monocyclic unsaturated hydrocarbon group with oneor more double bond(s) between carbon atoms, and includes, for example,“C₅₋₆ cycloalkenyl”, which means cycloalkenyl with 5 to 6 of carbonatoms.

A preferable “C₅₋₆ cycloalkenyl” is “C₅₋₆ cycloalkenyl” with one doublebond between carbon atoms.

An illustrative example of “C₅₋₆ cycloalkenyl” includes, for example,cyclopentenyl and cyclohexenyl. A preferable one is cyclopent-1-enyl orcyclohex-1-enyl.

“Spiro cycloalkyl” means a cyclic saturated hydrocarbon group with oneSpiro atom, and includes, for example, “spiro C₆₋₁₁ cycloalkyl”, whichmeans Spiro cycloalkyl with one Spiro atom and 6 to 11 of carbon atoms.

An illustrative example of “spiro C₆₋₁₁ cycloalkyl” includes, forexample, Spiro [3.3]heptyl, spiro [4.4]nonyl, and Spiro [5.5]undecyl. Apreferable one is spiro [3.3]heptyl.

“Alkylcarbonyl” means “alkyl”-attached carbonyl, and includes “C₁₋₃alkylcarbonyl”.

An illustrative example of “C₁₋₃ alkylcarbonyl” includes carbonyl whichattaches to the “C₁₋₃ alkyl”. A preferable one is methylcarbonyl.

“Alkylsulfanyl” means “alkyl”-attached sulfanyl, and includes “C₄₋₆alkylsulfanyl”.

An illustrative example of “C₄₋₆ alkylsulfanyl” includes sulfanyl whichattaches to the “C₄₋₆ alkyl”. A preferable one is isobutylsulfanyl orisopentylsulfanyl.

“Alkylsulfinyl” means “alkyl”-attached sulfinyl, and includes “C₄₋₆alkylsulfinyl”.

An illustrative example of “C₄₋₆ alkylsulfinyl” includes sulfinyl whichattaches to the “C₄₋₆ alkyl”. A preferable one is isobutylsulfinyl orisopentylsulfinyl.

“Alkylsulfonyl” means “alkyl”-attached sulfonyl, and includes “C₁₋₃alkylsulfonyl”, “C₁₋₄ alkylsulfonyl”, and “C₄₋₆ alkylsulfonyl”.

An illustrative example of “C₁₋₃ alkylsulfonyl” includes sulfonyl whichattaches to the “C₁-3 alkyl”. A preferable one is methylsulfonyl.

An illustrative example of “C₁₋₄ alkylsulfonyl” includes sulfonyl whichattaches to the “C₁₋₄ alkyl”. A preferable one is methylsulfonyl.

An illustrative example of “C₄₋₆ alkylsulfonyl” includes sulfonyl whichattaches to the “C₄₋₆ alkyl”. A preferable one is isobutylsulfonyl orisopentylsulfonyl.

“C₁₋₆ alkyl substituted with one C₁₋₄ alkylsulfonyl” means “alkyl”, with1 to 6 of carbon atom(s), substituted at any position with one C₁₋₄alkylsulfonyl. In particular, it includes, for example,2-methylsulfonylethyl.

“Alkoxycarbonyl” means carbonyl which attaches to “alkoxy”, andincludes, for example, “C₁₋₃ alkoxycarbonyl”.

An illustrative example of “C₁₋₃ alkoxycarbonyl” includes, for example,methoxycarbonyl, ethoxycarbonyl, and propoxycarbonyl. A preferable oneis ethoxycarbonyl.

“Cycloalkylsulfanyl” means “cycloalkyl”-attached sulfanyl, and includes“C₃₋₆ cycloalkylsulfanyl”.

An illustrative example of “C₃₋₆ cycloalkylsulfanyl” includes sulfanylwhich attaches to the “C₃₋₆ cycloalkyl”. A preferable one iscyclopentylsulfanyl.

“Cycloalkylsulfinyl” means “cycloalkyl”-attached sulfinyl, and includes“C₃₋₆ cycloalkylsulfinyl”.

An illustrative example of “C₃₋₆ cycloalkylsulfinyl” includes, forexample, sulfinyl which attaches to the “C₃₋₆ cycloalkyl”. A preferableone is cyclopentylsulfinyl.

“Cycloalkylsulfonyl” means “cycloalkyl”-attached sulfonyl, and includes“C₃₋₆ cycloalkylsulfonyl”.

An illustrative example of “C₃₋₆ cycloalkylsulfanyl” includes sulfonylwhich attaches to the “C₃₋₆ cycloalkyl”. A preferable one iscyclopentylsulfonyl.

“Alkylene” means a divalent group derived from straight or branchedchain saturated hydrocarbon, and includes, for example, “C₁₋₃ alkylene”and “C₁₋₆ alkylene”, each of which means alkylene with 1 to 3 of carbonatom(s) and 1 to 6 of carbon atom(s), respectively.

An illustrative example of “C₁₋₃ alkylene” includes, for example,methylene, ethylene, trimethylene, and —C(CH₃)₂—. A preferable one ismethylene or ethylene.

An illustrative example of “C₁₋₆ alkylene” includes, for example,methylene, ethylene, trimethylene, butylene, pentylene, hexylene,—C(CH₃)₂—, —C(CH₃)₂—CH₂—, —(CH₂)₂—CH(CH₃)—, —CH₂—C(CH₃)₂—CH₂—,—(CH₂)₃—C(CH₃)₂—, and —(CH₂)₂—C(CH₃)₂—. A preferable one is methylene,ethylene, trimethylene, butylene, —C(CH₃)₂—, —C(CH₃)₂—CH₂—,—(CH₂)₂—CH(CH₃)—, —CH₂—C(CH₃)₂—CH₂—, —(CH₂)₃—C(CH₃)₂— or—(CH₂)₂—C(CH₃)₂—.

“C₁₋₆ alkylene optionally substituted with one hydroxy” means “C₁₋₆alkylene substituted with one hydroxy” or “unsubstituted C₁₋₆ alkylene”.

“Cycloalkylene” means a divalent group derived from monocyclic saturatedhydrocarbon, and includes, for example, “C₃₋₆ cycloalkylene”, whichmeans cycloalkylene with 3 to 6 of carbon atoms.

An illustrative example of “C₃₋₆ cycloalkylene” includes, for example,cyclopropylene, cyclobutylene, cyclopentylene, and cyclohexylene. Apreferable “C₃₋₆ cycloalkylene” is “C₄_6 cycloalkylene”.

“Cross-linked cycloalkylene” means a divalent group derived frompolycyclic saturated hydrocarbon with a cross-linked structure of carbonatoms, and includes, for example, “cross-linked C₅₋₈ cycloalkylene”,which means cross-linked cycloalkylene with 5 to 8 of carbon atoms.

An illustrative example of “cross-linked C₅₋₈ cycloalkylene” includes,for example, bicyclo [1.1.1]pentylene, bicyclo[2.1.1]hexylene,bicyclo[2.2.1]heptylene, and bicyclo[2.2.2]octylene. A preferable“cross-linked C₅₋₈ cycloalkylene” is “cross-linked C₅₋₆ cycloalkylene”,in particular bicyclo[1.1.1]pentylene or bicyclo[2.1.1]hexylene.

“Phenylene substituted with one halogen” means phenylene substituted atany position with one halogen. In particular, it includes, for example,2-fluorophenylene and 4-fluorophenylene.

“Phenylene substituted with one C₁₋₃ alkyl” means phenylene substitutedat any position with one C₁₋₃ alkyl. In particular, it includes, forexample, 2-methylphenylene and 3-methylphenylene.

“Phenylene substituted with one C₁₋₃ alkoxy” means phenylene substitutedat any position with one C₁₋₃ alkoxy. In particular, it includes, forexample, 2-methoxyphenylene and 3-methoxyphenylene.

“Phenylene substituted with one trifluoromethyl” means phenylencsubstituted at any position with one trifluoromethyl. In particular, itincludes, for example, 3-trifluorophenylene.

“Pyrrolidinediyl substituted with one carboxy” means pyrrolidinediylsubstituted at any position with one carboxy. In particular, itincludes, for example, 3-carboxypyrrolidine-1,4-diyl.

“Pyrrolidinediyl substituted with one C₁₋₃ alkylcarbonyl” meanspyrrolidinediyl substituted at any position with one C₁₋₃ alkylcarbonyl.In particular, it includes, for example,1-methylcarbonylpyrrolidine-3,4-diyl.

“Pyrrolidinediyl substituted with one C₁₋₃ alkylsulfonyl” meanspyrrolidinediyl substituted at any position with one C₁₋₃ alkylsulfonyl.In particular, it includes, for example,1-methylsulfonylpyrrolidine-3,4-diyl.

“Pyrazolediyl substituted with one C₁₋₃ alkyl” means pyrazolediylsubstituted at any position with one C₁₋₃ alkyl. In particular, itincludes, for example, 1-methylpyrazole-3,5-diyl.

Embodiments of each group in the above formulae are illustrated asbelow.

A preferable “C₄₋₈ alkyl” in R¹ particularly includes butyl, isobutyl,sec-butyl, tert-butyl, 1-methylpropyl, pentyl, isopentyl, neopentyl,1,2-dimethylpropyl, 1-ethylpropyl, hexyl, isohexyl,1,2,2-trimethylpropyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl,3,3-dimethylbutyl, 2-ethylbutyl, heptyl, 4,4-dimethylpentyl,1-methyl-3,3-dimethylbutyl, octyl, and 2-propylpentyl. A furtherpreferable one is butyl, isobutyl, pentyl, isopentyl, 3,3-dimethylbutyl,2-ethylbutyl, 4,4-dimethylpentyl, 1-methyl-3,3-dimethylbutyl or2-propylpentyl.

A preferable “C₄₋₈ alkenyl” in R¹ is “C₄₋₆ alkenyl”, and particularlyincludes 2-methyl-propenyl, 3,3-dimethyl-but-1-enyl, and3-methyl-but-2-enyl. A further preferable one is 2-methyl-propanol or3,3-dimethyl-but-1-enyl.

A preferable “C₄₋₈ alkynyl” is R¹ is “C₄₋₆ alkynyl”, and particularlyincludes 3,3-dimethyl-but-1-ynyl, and 3-methyl-but-1-ynyl. A furtherpreferable one is “C₆ alkynyl”, in particular 3,3-dimethyl-but-1-ynyl.

A preferable “C₃₋₇ alkyl substituted with one trifluoromethyl” in R¹ is“C₃₋₅ alkyl substituted with one trifluoromethyl”, and particularlyincludes 4,4,4-trifluorobutyl, 5,5,5-trifluoropentyl,6,6,6-trifluorohexyl, and 4,4,4-trifluoro-3,3-dimethylbutyl. A furtherpreferable one is 4,4,4-trifluorobutyl or4,4,4-trifluoro-3,3-dimethylbutyl.

A preferable “C₁₋₄ alkyl” in “C₁₋₄ alkyl substituted with onesubstituent selected from Group X^(a1), in R¹ is “C₁₋₂ alkyl”, inparticular methyl or ethyl.

A preferable “C₃₋₆ alkoxy” in R¹ is “C₄₋₆ alkoxy”, and particularlyincludes propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy,tert-butoxy, pentyloxy, isopentyloxy, 2-methylbutoxy,1,1-dimethylpropoxy, neopentyloxy, 3,3-dimethylbutoxy, 1-ethylpropoxy,and hexyloxy. A further preferable one is isobutoxy, isopentyloxy,neopentyloxy or 3,3-dimethylbutoxy.

A preferable “C₂₋₇ alkoxy substituted with one trifluoromethyl” in R¹ is“C₂ alkoxy substituted with one trifluoromethyl”, in particular3,3,3-trifluoropropoxy.

A preferable “C₁₋₃ alkoxy” in “C₁₋₃ alkoxy substituted with onesubstituent selected from Group X^(a2)” in R¹ is “C₁₋₂ alkoxy”, inparticular methoxy or ethoxy.

A preferable “C₄₋₆ cycloalkyl” in R¹ is in particular cyclobutyl,cyclopentyl or cyclohexyl.

A preferable “C₃₋₆ cycloalkyl substituted with one to two C₁₋₄ alkyl” inR¹ is “C₃₋₆ cycloalkyl substituted with the same or different one or twoC₁₋₄ alkyl”, more preferably “cyclopropyl or cyclohexyl substituted withthe same or different one or two methyl, isopropyl or tert-butyl”. Inparticular, it is 2-isopropylcyclopropyl, 2-tert-butylcyclopropyl or3,3-dimethylcyclohexyl.

A preferable “C₅₋₆ cycloalkenyl optionally substituted with one to twoC₁₋₄ alkyl” in R¹ is “C₅₋₆ cycloalkenyl optionally substituted with thesame or different two C₁₋₄ alkyl”, more preferably “1-cyclopentenyl or1-cyclohexenyl, optionally substituted with the same or different twomethyl”. In particular, it is 1-cyclopentenyl, 1-cyclohexenyl,3,3-dimethylcyclohex-1-enyl or 4,4-dimethylcyclohex-1-enyl.

A preferable “spiro C₆₋₁₁ cycloalkyl” in R¹ is “spiro C₆₋₈ cycloalkyl”,more preferably “spiro C₇ cycloalkyl”. In particular, it is Spiro[3.3]heptyl.

A preferable “C₁₋₃ alkoxycarbonyl” in R¹ is “C₁₋₂ alkoxycarbonyl”, morepreferably ethoxycarbonyl.

A preferable “halogen” in R² is fluoro or chloro.

A preferable “C₁₋₆ alkyl” in R² is “C₁₋₂ alkyl”, more preferably methyl.

A preferable “C₁₋₃ alkoxy optionally substituted with phenyl” in R² is“C₁₋₂ alkoxy optionally substituted with phenyl”, more preferablybenzyloxy.

A preferable “n” is an integer of 0 to 2. In Formula [I], the followingpartial structure:

includes the following embodiments.

A further preferable “n” is an integer of 1 or 2. In Formula [I], thefollowing partial structure:

includes the following embodiments.

In the above embodiments, when R² is halogen, the following moieties areillustrated.

The above structure also includes the following embodiments.

An embodiment of “R¹ and R² may combine together with the benzene ringto which they attach to form indanyl where the indanyl may besubstituted with the same or different one to two C₁₋₆ alkyl” includes,when “n” is 1, the following embodiments.

A preferable “—Y^(b)—COO—R³⁰” in R³ is —(C₃₋₅ alkylene)—COOH or —C₄cycloalkylene-COOH, in particular —C(CH₃)₂—COOH, —C(CH₃)₂—CH₂—COOH,—C(CH₃)₂—(CH₂)₂—COOH or -cyclobutylene-COOH.

“C₁₋₆ alkyl optionally substituted with one hydroxy” in R³ is “C₁₋₆alkyl substituted with one hydroxy” or “unsubstituted C₁₋₆ alkyl”. Apreferable “C₁₋₆ alkyl substituted with one hydroxy” is “C₆ alkylsubstituted with one hydroxy”. An illustrative example of “C₁₋₆ alkyloptionally substituted with one hydroxy” includes methyl, ethyl,isopropyl, isobutyl, tert-butyl, 1-methylpropyl, isopentyl, neopentyl or4-hydroxy-1,1-dimethylbutyl.

A preferable “C₃₋₆ cycloalkyl optionally substituted with the same ordifferent one to three substituent(s) selected from Group X^(b)” in R³is “C₃₋₆ cycloalkyl optionally substituted with the same or differentone to two substituent(s) selected from fluoro or methyl”, in particularcyclopropyl, cyclobutyl, 1-methylcyclopropyl, 3,3-difluorocyclobutyl orcyclohexyl.

One preferable embodiment of R³ is —Y^(b)—COO—R³⁰, and includes any ofthe following structures.

Another preferable embodiment of R³ is —Y^(b)—COO—R³⁰ wherein Y^(b) is

and in this case, one preferable embodiment of Formula [I] includes anembodiment having the following structure,

A preferable R⁴ is hydrogen.

An illustrative example of “C₁₋₆ alkylene optionally substituted withone hydroxy” in Y^(c) in “—Y^(c)—COO—R⁵⁰” in R⁵ includes, for example,methylene, ethylene, trimethylene, butylene, (CH₂)₂—CH(CH₃),CH(CH₃)—(CH₂)₂, (CH₂)₂—C(CH₃)₂, CH₂—C(CH₃)₂—CH₂, C(CH₃)₂—(CH₂)₂,(CH₂)₃—C(CH₃)₂, and (CH₂)₂—CH(OH).

A preferable m is an integer of 0 to 2, and a preferable w is an integerof 0 to 1.

A preferable “(CH₂)_(m)—Y^(c1)—(CH₂)_(w)” in Y^(c) in “—Y^(c1)—COO—R⁵⁰”in R⁵ is Y^(c1), Y^(c1)—CH₂, CH₂—Y^(c1), CH₂—Y^(c1)—CH₂, (CH₂)₂—Y^(c1)or (CH₂)₂—Y^(c1)—CH₂.

A preferable “C₃₋₆ cycloalkylene optionally substituted with one C₁₋₃alkyl” in Y^(c1) is “cyclopropylene, cyclobutylene, cyclopentylene orcyclohexylene, optionally substituted with one methyl”.

A preferable “cross-linked C₅₋₈ cycloalkylene” in Y^(c1) is“cross-linked C₅ cycloalkylene”, and for example has the followingstructure.

When Y^(c1) is

one preferable embodiment of Formula [I] includes embodiments having thefollowing structures in the case where m is 0 and w is 0.

In this case, a preferable R⁵⁰ is hydrogen or methyl.

When Y¹ is “pyrazolediyl substituted with one C₁₋₃ alkyl”, onepreferable embodiment of Formula [I] includes an embodiment having thefollowing structure in the case where m is 0 and w is 0.

In this case, a preferable R⁵⁰ is hydrogen or methyl.

When Y¹ is “isoxazolediyl”, one preferable embodiment of Formula [I]includes an embodiment having the following structure in the case wherem is 0 and w is 0.

In this case, a preferable R⁵⁰ is hydrogen or methyl.

A preferable “C₁₋₄ alkyl optionally substituted with one C₁₋₃ alkoxy” inR⁵ is “C₁₋₃ alkyl optionally substituted with one C₁₋₃ alkoxy”, morepreferably “ethyl or isopropyl, optionally substituted with onemethoxy”. In particular, it is methoxyethyl or isopropyl.

A preferable “C₃₋₆ cycloalkyl optionally substituted with onehydroxy-C₁₋₄ alkyl” in R⁵ is “cyclobutyl optionally substituted with onehydroxymethyl”. In particular, it is cyclobutyl or3-hydroxymethylcyclobutyl.

One preferable embodiment of R⁵ is —Y^(c)—COO—R⁵⁰, and includes any ofthe following structures.

A preferable R⁶ is methyl.

In [01], the expression “when R⁵ is —Y^(c)—COO—R⁵⁰, Y^(c) is(CH₂)_(m)—Y^(c1)—(CH₂)_(w), m and w are 0, and Y^(c1) is phenylene, thenR⁶ is methyl” means an embodiment where R⁶ is methyl when R⁵ moietyattaches to a dihydropyrimidine ring via phenylene. An illustrativeexample includes the following embodiment.

In [01], the expression “either R³ or R⁵ or both of them have “—COO—”includes the following embodiments.

An embodiment where when R³ is (1) —Y^(b)—COO—R³⁰, then R⁵ is

-   -   (1) Y^(c)—COO—R⁵⁰    -   (2) hydrogen,    -   (3) C₁₋₄ alkyl optionally substituted with one C₁₋₃ alkoxy or    -   (4) C₃₋₆ cycloalkyl optionally substituted with one hydroxy-C₁₋₄        alkyl; or an embodiment where when R³ is    -   (1) C₁₋₆ alkyl optionally substituted with one hydroxy,    -   (2) C₃₋₆ cycloalkyl optionally substituted with the same or        different one to three substituent(s) selected from Group X^(b),    -   (3)

-   -    or    -   (4)

-   -   then R⁵ is (1) —Y^(c)—COO—R⁵⁰.

A compound of Formula [I] includes any compound of the following Formula[II], [III] or [VI].

One preferable embodiment of the compound of Formula [I] includes thecompounds of the following general formulae.

Each symbol in the following each formula has the same meaning asdefined in the above [01] unless otherwise specified.

Another preferable embodiment of the compound of Formula [I] is acompound of Formula [I],

-   -   wherein R¹ is    -   (1) C₄₋₈ alkyl,    -   (2) C₄₋₆ alkenyl,    -   (3) C₄₋₆ alkynyl,    -   (4) C₃₋₅ alkyl substituted with one trifluoromethyl,    -   (5) C₁₋₄ alkyl substituted with one substituent selected from        Group X^(a1),    -   (6) C₃₋₆ alkoxy,    -   (7) C₂₋₇ alkoxy substituted with one trifluoromethyl,    -   (8) C₁₋₃ alkoxy substituted with one substituent selected from        Group X^(a2),    -   (9) C₄₋₆ cycloalkyl,    -   (10) C₃₋₆ cycloalkyl substituted with one to two C₁₋₄ alkyl,    -   (11) C₅₋₆ cycloalkenyl optionally substituted with one to two        C₁₋₄ alkyl,    -   (12) spiro C₆₋₈ cycloalkyl or    -   (13) C₁₋₃ alkoxycarbonyl;    -   Group X^(a1) is    -   (a) C₃₋₆ cycloalkyl optionally substituted with the same or        different one to three C₁₋₅ alkyl,    -   (b) phenyl,    -   (c) C₂₋₄ alkoxy, and    -   (d) trimethylsilyl;    -   Group X^(a2) is    -   (a) C₃₋₆ cycloalkyl,    -   (b) phenyl, and    -   (c) C₁₋₄ alkoxy;    -   R² is    -   (1) halogen,    -   (2) C₁₋₆ alkyl or    -   (3) C₁₋₃ alkoxy optionally substituted with phenyl;    -   n is an integer of 0, 1 or 2, provided that when n is 2, each R²        may be different with each other; or    -   R¹ and R² may combine together with the benzene ring to which        they attach to form indanyl where the indanyl may be substituted        with the same or different one to two C₁₋₆ alkyl;    -   R³ is    -   (1) —Y^(b)—COO—R³⁰,    -   (2) C₁₋₆ alkyl optionally substituted with one hydroxy,    -   (3) C₃₋₆ cycloalkyl optionally substituted with the same or        different one to three substituent(s) selected from Group X^(b),    -   (4)

-   -    or    -   (5)

-   -   Y^(b) is    -   (a) C₁₋₆ alkylene or (b) C₄₋₆ cycloalkylene;    -   R³⁰ is    -   (a) hydrogen or (b) C₁₋₄ alkyl;    -   Group X^(b) is    -   (a) halogen and    -   (b) C₁₋₆ alkyl;    -   R⁴ is    -   (1) hydrogen or (2) methyl;    -   R⁵ is    -   (1) —Y^(c)—COO—R⁵⁰    -   (2) hydrogen,    -   (3) C₁₋₄ alkyl optionally substituted with one C₁₋₃ alkoxy or    -   (4) C₃₋₆ cycloalkyl optionally substituted with one hydroxy-C₁₋₄        alkyl;    -   Y^(c) is    -   (a) C₁₋₆ alkylene optionally substituted with one hydroxy,    -   (b) CH₂—CH₂—O—CH₂ or    -   (c) (CH₂)_(m)—Y^(c1)—(CH₂)_(w);    -   m is an integer of 0, 1 or 2;    -   w is an integer of 0, 1 or 2;    -   Y^(c1) is    -   (a) C₄₋₆ cycloalkylene optionally substituted with one C₁₋₃        alkyl,    -   (b) phenylene,    -   (c) cross-linked C₅₋₆ cycloalkylene or    -   (d)

-   -   R⁵⁰ is    -   (a) hydrogen or (b) C₁₋₄ alkyl;    -   R⁶ is    -   (1) hydrogen or (2) methyl,    -   provided that    -   when R⁵ is —Y^(c)—COO—R⁵⁰, Y^(c) is (CH₂)_(m)—Y^(c1)—(CH₂)_(w),        m and w are 0, and Y^(c1) is phenylene, then    -   R⁶ is methyl; and    -   either R³ or R⁵ or both of them have “—COO—”.

Another preferable embodiment of the compound of Formula [I] is acompound of Formula [I],

-   -   wherein R¹ is    -   (1) C₄₋₈ alkyl,    -   (2) C₄₋₆ alkenyl,    -   (3) C₆ alkynyl,    -   (4) trifluoromethyl-C₃₋₅ alkyl,    -   (5) C₁₋₂ alkyl substituted with one substituent selected from        Group X^(a1),    -   (6) C₄₋₆ alkoxy,    -   (7) trifluoromethyl-C₂ alkoxy,    -   (8) C₁₋₂ alkoxy substituted with one substituent selected from        Group X^(a2),    -   (9) C₄₋₆ cycloalkyl,    -   (10) C₃₋₆ cycloalkyl substituted with one to two C₁₋₄ alkyl.    -   (11) C₅₋₆ cycloalkenyl optionally substituted with one to two        C₁₋₄ alkyl,    -   (12) spiro C₇ cycloalkyl or    -   (13) ethoxycarbonyl;    -   Group X^(a1) is    -   (a) C₃₋₆ cycloalkyl optionally substituted with one to two        methyl,    -   (b) phenyl,    -   (c) C₃₋₄ alkoxy, and    -   (d) trimethylsilyl;    -   Group X^(a2) is    -   (a) cyclohexyl,    -   (b) phenyl, and    -   (c) methoxy;    -   R² is    -   (1) fluoro or chloro,    -   (2) C₁₋₆ alkyl or    -   (3) methoxy optionally substituted with phenyl;    -   n is an integer of 0, 1 or 2, provided that n is 2, each R² may        be different with each other; or R¹ and R² may combine together        with the benzene ring to which they attach to form indanyl        optionally substituted with two methyl;    -   R³ is    -   (1) —Y^(b)—COO—R³⁰    -   (2) C₁₋₆ alkyl optionally substituted with one hydroxy,    -   (3) C₃₋₆ cycloalkyl optionally substituted with the same or        different one to two substituent(s) selected from Group X^(b),    -   (4)

-   -    or    -   (5)

-   -   Y^(b) is    -   (a) C₃₋₅ alkylene or (b) C₄ cycloalkylene;    -   R³⁰ is hydrogen;    -   Group X^(b) is    -   (a) fluoro and    -   (b) methyl;    -   R⁴ is    -   (1) hydrogen or (2) methyl;    -   R⁵ is    -   (1) —Y^(c)—COO—R⁵⁰,    -   (2) hydrogen,    -   (3) C₂₋₃ alkyl optionally substituted with one C₁₋₃ alkoxy or    -   (4) C₄ cycloalkyl optionally substituted with one hydroxy-C₁₋₄        alkyl;    -   Y^(c) is    -   (a) C₁₋₆ alkylene optionally substituted with one hydroxy,    -   (b) CH₂—CH₂—O—CH₂ or    -   (c) (CH₂)_(m)—Y^(c1)—(CH₂)_(w);    -   m is an integer of 0, 1 or 2;    -   w is an integer of 0 or 1;    -   Y^(c1) is    -   (a) C₃₋₆ cycloalkylene optionally substituted with one methyl,    -   (b) phenylene,    -   (c) cross-linked C₅ cycloalkylene or    -   (d)

-   -   R⁵⁰ is    -   (a) hydrogen or (b) methyl;    -   R⁶ is    -   (1) hydrogen or (2) methyl,    -   provided that    -   when R⁵ is —Y^(c)—COO—R⁵⁰, Y, is (ethylene)-Y^(c1)-(methylene),        and Y^(c1) is phenylene, then R⁶ is methyl; and either R³ or R⁵        or both of them have “—COO—”.

Another preferable embodiment of the compound of Formula [I] is acompound of the following Formula [II]:

-   -   wherein    -   R¹ is    -   (1) C₄₋₈ alkyl,    -   (2) C₃₋₆ alkoxy or    -   (3) C₅₋₆ cycloalkenyl optionally substituted with one to two        C₁₋₄ alkyl;    -   R² is fluoro or chloro;    -   n is 1;    -   R³ is C₁₋₆ alkyl;    -   R⁴ is    -   (1) hydrogen or (2) methyl;    -   Y^(c) is C₁₋₆ alkylene;    -   R⁵⁰ is    -   (a) hydrogen or (b) C₁₋₄ alkyl;    -   R⁶ is    -   (1) hydrogen or (2) methyl.

A more preferable embodiment of the compound of Formula [I] is acompound of Formula [II-A] which R⁶ is methyl in Formula [II]:

Another more preferable embodiment of the compound of Formula [I] is acompound of Formula [II-B] which R⁴ is hydrogen and R⁶ is methyl inFormula [II]:

Another preferable embodiment of the compound of Formula [I] is acompound of Formula [III]:

-   -   wherein    -   R¹ is    -   (1) C₄₋₈ alkyl,    -   (2) C₃₋₆ alkoxy or    -   (3) C₅₋₆ cycloalkenyl optionally substituted with one to two        C₁₋₄ alkyl;    -   R² is fluoro or chloro;    -   n is 1;    -   Y^(b) is C₁₋₆ alkylene;    -   R³⁰ is    -   (a) hydrogen or (b) C₁₋₄ alkyl;    -   R⁴ is    -   (1) hydrogen or (2) methyl;    -   R⁵ is    -   (1) hydrogen,    -   (2) C₁₋₄ alkyl optionally substituted with one C₁₋₃ alkoxy or    -   (3) C₃₋₆ cycloalkyl optionally substituted with one hydroxy-C₁₋₄        alkyl;    -   R⁶ is    -   (1) hydrogen or (2) methyl.

A more preferable embodiment of the compound of Formula [I] is acompound of Formula [III-A] which R⁶ is methyl in Formula [III]:

Another more preferable embodiment of the compound of Formula [I] is acompound of Formula [HI-B] which R⁴ is hydrogen and R⁶ is methyl inFormula [III]:

Another preferable embodiment of the compound of Formula [I] is acompound of the following Formula [IV]:

A more preferable embodiment of the compound of Formula [I] is acompound of Formula [IV-A] which R⁶ is methyl in Formula [IV]:

Another more preferable embodiment of the compound of Formula [I] is acompound of Formula [IV-B] which R⁴ is hydrogen and R⁶ is methyl inFormula [IV]:

Another more preferable embodiment is a compound of the followingformula:

Another preferable embodiment of the compound of Formula [I] is acompound of Formula [IV-D] which R⁴ is hydrogen in Formula [IV]:

Another preferable embodiment of the compound of Formula [I] is acompound of the following Formula [E-IV]:

A more preferable embodiment of the compound of Formula [I] is acompound of Formula [E-IV-A] which R⁶ is methyl in Formula [E-IV]:

Another more preferable embodiment of the compound of Formula [I] is acompound of Formula [E-IV-B] which R⁴ is hydrogen in Formula [E-IV-A]:

A particularly preferable embodiment of the compound of Formula [E-IV]is a compound of the following formula:

Another preferable embodiment of the compound of Formula [I] is acompound of the following Formula [V]:

-   -   wherein    -   R^(3a) is    -   (1) hydrogen or    -   (2) C₁₋₆ alkyl optionally substituted with the same or different        one to three substituent(s) selected from the group consisting        of hydroxy, halogen, hydroxycarbonyl, and C₁₋₃ alkoxycarbonyl;    -   R^(3b) is    -   (1) hydrogen or (2) C₁₋₆ alkyl;    -   R^(3c) is    -   (1) hydrogen or (2) C₁₋₆ alkyl; and the other symbols have the        same meanings as defined in [01], provided that when R⁵ is        —Y—COO—R⁵⁰, Y^(c) is (CH₂)_(m)—Y^(c1)—(CH₂)_(w), m and w are 0,        and Y^(c1) is phenylene, then R⁶ is methyl; and    -   either a structure of the formula:

-   -   or R⁵ or both of them have “—COO—”.

Another embodiment of the compound of Formula [V] is the followingcompound:

-   -   wherein    -   R^(3a) and R^(3b) may combine together with the carbon atom to        which they attach to form    -   (1) a C₃₋₆ cycloalkane ring optionally substituted with the same        or different one to three substituent(s) selected from the group        consisting of hydroxy, halogen, hydroxycarbonyl, and C₁₋₃        alkoxycarbonyl,    -   (2) a tetrahydropyran ring or    -   (3) a 1-methanesulfonylazetidine ring;    -   R^(3c) is (1) hydrogen or (2) C₁₋₆ alkyl; and the other symbols        have the same meanings as defined in [01],    -   provided that    -   when R⁵ is —Y—COO—R⁵⁰, Y^(c) is (CH₂)_(m)—Y^(c1)—(CH₂)_(w), m        and w are 0, and Y^(c1) is phenylene, then    -   R⁶ is methyl;    -   either a structure of the formula:

-   -   or R⁵ or both of them have “—COO—”.

A more preferable embodiment of the compound of Formula [V] includes thecompounds of the following general formulae.

Another preferable embodiment of the compound of Formula [I] is acompound of the following Formula [VI]:

A further preferable embodiment of a compound of Formula [I] is any oneof compounds of the following formulae:

-   -   wherein    -   R^(3h) is hydrogen or methyl;    -   R^(3w) is methyl or fluoro;    -   n^(x) is an inter of 0 or 2;    -   n^(w) is an integer of 0, 1, 2 or 3; and    -   the other symbols have the same meanings as defined in [01].

In the Formulae [IV-B-A] to [IV-B-D], a more preferable one is any oneof compounds wherein R² is chloro or trifluoromethyl.

In the Formulae [IV-B-A] to [IV-B-D], a still more preferable one is anyone of compounds wherein

-   -   Y^(c) is    -   (a) C₁₋₆ alkylene optionally substituted with one hydroxy or    -   (b) (CH₂)_(m)—Y^(c1)—(CH₂)_(w);    -   m is an integer of 0, 1 or 2;    -   w is an integer of 0, 1 or 2; and    -   Y^(c1) is    -   (a) C₃₋₆ cycloalkylene optionally substituted with one C₁₋₃        alkyl,    -   (b) phenylene,    -   (c) phenylene substituted with one halogen,    -   (d) phenylene substituted with one C₁₋₃ alkyl,    -   (e) phenylene substituted with one C₁₋₃ alkoxy,    -   (f) phenylene substituted with one trifluoromethyl,    -   (g) cross-linked C₅₋₈ cycloalkylene,    -   (h) pyrrolidinediyl,    -   (i) pyrrolidinediyl substituted with one carboxy,    -   (j) pyrrolidinediyl substituted with one C₁₋₃ alkylcarbonyl,    -   (k) pyrrolidinediyl substituted with one C₁₋₃ alkylsulfonyl or    -   (l) pyridinediyl.

A still more preferable one is any one of compounds of Formula [IV-B-A]to [IV-B-D]

-   -   wherein    -   Y^(c) is C₁₋₆ alkylene, phenylene, cross-linked C₅₋₈        cycloalkylene or pyridinediyl.

Another further preferable embodiment of a compound of Formula [I] isany one of compounds of the following formulae:

-   -   wherein    -   R³ is C₁₋₆ alkyl optionally substituted with one hydroxy,

C₁₋₆ alkyl substituted with one C₁₋₄ alkoxy or C₃₋₆ cycloalkyloptionally substituted with the same or different one to threesubstituent(s) selected from Group X^(b);

-   -   R^(5B) is hydrogen, halogen, C₁₋₃ alkyl, C₁₋₃ alkoxy or        trifluoromethyl; and    -   the other symbols have the same meanings as defined in [01].

In the Formulae [IV-B-A] to [IV-B-N], a more preferable one is any oneof compounds

-   -   wherein    -   R¹ is    -   C₄₋₈ alkyl,    -   C₃₋₇ alkyl substituted with one trifluoromethyl,    -   C₁₋₅ alkyl substituted with one substituent selected from Group        X^(a1),    -   C₃₋₆ alkoxy,    -   C₂₋₇ alkoxy substituted with one trifluoromethyl,    -   C₁₋₃ alkoxy substituted with one substituent selected from Group        X^(a2),    -   C₄₋₆ cycloalkyl,    -   C₃₋₆ cycloalkyl substituted with the same or different one to        two C₁₋₅ alkyl,    -   C₅₋₆ cycloalkenyl optionally substituted with the same or        different one to two C₁₋₄ alkyl, cyclohexylidenemethyl        optionally substituted with the same or different one to two        C₁₋₃ alkyl, tetrahydropyran-4-ylidenemethyl,    -   C₃₋₆ cycloalkyl substituted with one to the same two halogen or    -   C₅₋₆ cycloalkenyl substituted with one to the same two halogen;        and    -   R² is fluoro, chloro or trifluoromethyl.

In the Formulae [IV-B-A] to [IV-B-N], a still more preferable one is anyone of compounds wherein

-   -   R¹ is    -   C₄₋₈ alkyl,    -   C₃₋₇ alkyl substituted with one trifluoromethyl,    -   C₁₋₅ alkyl substituted with one substituent selected from Group        X^(a1),    -   C₃₋₆ alkoxy,    -   C₄₋₆ cycloalkyl substituted with the same or different one to        two C₁₋₆ alkyl,    -   C₅₋₆ cycloalkenyl optionally substituted with the same or        different one to two C₁₋₄ alkyl,    -   C₆ cycloalkyl substituted with one to the same two halogen or    -   C₆ cycloalkenyl substituted with one to the same two halogen;        and    -   R² is chloro or trifluoromethyl.

In a still more preferable embodiment of the Formulae [IV-B-A] to[IV-B-N], R¹ is any one of the following substituents.

Another embodiment of the present invention also includes the followingembodiments. [01a] A compound of Formula [I] or a pharmaceuticallyacceptable salt thereof:

-   -   wherein    -   R¹ is    -   (1) C₄₋₈ alkyl,    -   (2) C₄₋₈ alkenyl,    -   (3) C₄₋₈ alkynyl,    -   (4) C₃₋₇ alkyl substituted with one trifluoromethyl,    -   (5) C₁₋₄ alkyl substituted with one substituent selected from.        Group X^(a1),    -   (6) C₃₋₆ alkoxy,    -   (7) C₂₋₇ alkoxy substituted with one trifluoromethyl,    -   (8) C₁₋₃ alkoxy substituted with one substituent selected from        Group X^(a2),    -   (9) C₄₋₆ cycloalkyl,    -   (10) C₃₋₆ cycloalkyl substituted with one to two C₁₋₄ alkyl,    -   (11) C₅₋₆ cycloalkenyl, optionally substituted with one to two        C₁₋₄ alkyl,    -   (12) spiro C₆₋₁₁ cycloalkyl or    -   (13) C₁₋₃ alkoxycarbonyl;    -   Group X^(a1) is    -   (a) C₃₋₆ cycloalkyl optionally substituted with the same or        different one to three C₁₋₅ alkyl,    -   (b) phenyl,    -   (c) C₂₋₄ alkoxy, and    -   (d) trimethylsilyl;    -   Group X^(a2) is    -   (a) C₃₋₆ cycloalkyl,    -   (b) phenyl, and    -   (c) C₁₋₄ alkoxy;    -   R² is    -   (1) halogen,    -   (2) C₁₋₆ alkyl, or    -   (3) C₁₋₃ alkoxy optionally substituted with phenyl;    -   n is an integer of 0, 1 or 2, provided that when n is 2, each R²        may be different with each other; or    -   R¹ and R² may combine together with the benzene ring to which        they attach to form indanyl where the indanyl may be substituted        with the same or different one to two C₁₋₆ alkyl;    -   R³ is    -   (1) —Y^(b)—COO—R³⁰,    -   (2) C₁₋₆ alkyl optionally substituted with one hydroxy,    -   (3) C₃₋₆ cycloalkyl optionally substituted with the same or        different one to three substituent(s) selected from Group X^(b),    -   (4)

-   -    or    -   (5)

-   -   Y^(b) is    -   (a) C₁₋₆ alkylene or (b) C₃₋₆ cycloalkylene;    -   R³⁰ is    -   (a) hydrogen or (b) C₁₋₄ alkyl;    -   Group X^(b) is    -   (a) halogen and    -   (b) C₁₋₆ alkyl;    -   R⁴ is    -   (1) hydrogen or (2) methyl;    -   R⁵ is    -   (1) —Y^(c)—COO—R⁵⁰,    -   (2) hydrogen,    -   (3) C₁₋₄ alkyl optionally substituted with one C₁₋₃ alkoxy or    -   (4) C₃₋₆ cycloalkyl optionally substituted with one hydroxy-C₁₋₄        alkyl;    -   Y^(c) is    -   (a) C₁₋₆ alkylene optionally substituted with one hydroxy,    -   (b) CH₂—CH₂—O—CH₂ or    -   (c) (CH₂)_(m)—Y^(c1)—(CH₂)_(w);    -   m is an integer of 0, 1 or 2;    -   w is an integer of 0, 1 or 2;    -   Y^(c1) is    -   (a) C₃₋₆ cycloalkylene optionally substituted with one C₁₋₃        alkyl,    -   (b) phenylene,    -   (c) cross-linked C₅₋₈ cycloalkylene or    -   (d)

-   -   R⁵⁰ is    -   (a) hydrogen or (b) C₁₋₄ alkyl;    -   R⁶ is    -   (1) hydrogen or (2) methyl;    -   provided that    -   when R⁵ is —Y^(c)—COO—R⁵⁰, is (CH₂)_(m)—Y^(c1)—(CH₂)_(w), in and        w are 0, and Y^(c1) is phenylene, then    -   R⁶ is methyl; and    -   either R³ or R⁵ or both of them have “—COO—”.    -   [02a] The compound of [Ola], wherein the compound of Formula [I]        is a compound of Formula [II], or a pharmaceutically acceptable        salt thereof.

-   -   [03a] The compound of [Ola], wherein the compound of Formula [I]        is a compound of Formula [III], or a pharmaceutically acceptable        salt thereof.

-   -   [04a] The compound of [Ola], wherein the compound of Formula [I]        is a compound of Formula [IV], or a pharmaceutically acceptable        salt thereof.

-   -   [05a] The compound of any one of [Ola] to [04a], wherein R⁶ is        methyl, or a pharmaceutically acceptable salt thereof.    -   [06a] The compound of any one of [Ola] to [05a], wherein R⁴ is        hydrogen, or a pharmaceutically acceptable salt thereof.    -   [07a] The compound of any one of [Ola] to [06a], wherein n is an        integer of 1 or 2, or a pharmaceutically acceptable salt        thereof.    -   [08a] The compound of any one of [Ola] to [07a], wherein R² is        halogen, or a pharmaceutically acceptable salt thereof.    -   [09a] The compound of [08a], wherein R² is chloro or fluoro, or        a pharmaceutically acceptable salt thereof.    -   [10a] The compound of [02a], wherein R⁵⁰ is hydrogen, or a        pharmaceutically acceptable salt thereof.    -   [11a] The compound of [03a], wherein R³⁰ is hydrogen, or a        pharmaceutically acceptable salt thereof    -   [12a] A pharmaceutical composition comprising the compound of        any one of [01a] to [11a] or a pharmaceutically acceptable salt        thereof and a pharmaceutically acceptable carrier.    -   [13a] An RORγ antagonist comprising the compound of any one of        [Ola] to [11a] or a pharmaceutically acceptable salt thereof and        a pharmaceutically acceptable carrier.    -   [14a] An agent for treating or preventing a disease selected        from the group consisting of autoimmune disease, allergic        disease, dry eye, fibrosis, and metabolic disease, comprising        the compound of any one of [01a] to [11a] or a pharmaceutically        acceptable salt thereof.    -   [15a] The agent of [14a], wherein the disease is autoimmune        disease.    -   [16a] The agent of [15a], wherein the autoimmune disease is        selected from the group consisting of rheumatoid arthritis,        psoriasis, inflammatory bowel disease such as Crohn's disease        and ulcerative colitis, multiple sclerosis, systemic lupus        erythematosus, ankylosing spondylitis, uveitis, polymyalgia        rheumatica, and type I diabetes.    -   [17a] The agent of [14a], wherein the disease is metabolic        disease.    -   [18a] The agent. of [17a], wherein the metabolic disease is        diabetes.    -   [19a] A method of inhibiting RORγ, comprising administering to a        mammal a therapeutically effective amount of the compound of any        one of [01a] to [11a] or a pharmaceutically acceptable salt        thereof.    -   [20a] A method of treating or preventing a disease selected from        the group consisting of autoimmune disease, allergic disease,        dry eye, fibrosis, and metabolic disease, comprising        administering to a mammal an effective amount of the compound of        any one of [01a] to [11a] or a pharmaceutically acceptable salt        thereof.    -   [21a] The method of [204 wherein the disease is autoimmune        disease.    -   [22a] The method of [21a], wherein the autoimmune disease is        selected from the group consisting of rheumatoid arthritis,        psoriasis, inflammatory bowel disease such as Crohn's disease        and ulcerative colitis, multiple sclerosis, systemic lupus        erythematosus, ankylosing spondylitis, uveitis, polymyalgia        rheumatica, and type I diabetes.    -   [23a] The method of [20a], wherein the disease is metabolic        disease.    -   [24a] The method of [23a], wherein the metabolic disease is        diabetes.    -   [25a] Use of the compound of any one of [Ola] to [11a] or a        pharmaceutically acceptable salt thereof for the manufacture of        an RORγ antagonist.    -   [26a] Use of the compound of any one of [Ola] to [11a] or a        pharmaceutically acceptable salt thereof for the manufacture of        an agent for treatment or prevention of a disease selected from        the group consisting of autoimmune disease, allergic disease,        dry eye, fibrosis, and metabolic disease.    -   [27a] The use of [26a], wherein the disease is autoimmune        disease.    -   [28a] The use of [27a], wherein the autoimmune disease is        selected from the group consisting of rheumatoid arthritis,        psoriasis, inflammatory bowel disease such as Crohn's disease        and ulcerative colitis, multiple sclerosis, systemic lupus        erythematosus, ankylosing spondylitis, uveitis, polymyalgia        rheumatica, and type I diabetes.    -   [29a] The use of [26a], wherein the disease is metabolic        disease.    -   [30a] The use of [29a], wherein the metabolic disease is        diabetes.    -   [31a] A compound of any one of [01a] to [11a] or a        pharmaceutically acceptable salt thereof for use as an RORγ        antagonist.    -   [32a] A compound of any one of [01a] to [11a] or a        pharmaceutically acceptable salt thereof for use as an agent for        treating or preventing a disease selected from the group        consisting of autoimmune disease, allergic disease, dry eye,        fibrosis, and metabolic disease.    -   [33a] The compound of [32a], wherein the disease is autoimmune        disease, or a pharmaceutically acceptable salt thereof.    -   [34a] The compound of [33a], wherein the autoimmune disease is        selected from the group consisting of rheumatoid arthritis,        psoriasis, inflammatory bowel disease such as Crohn's disease        and ulcerative colitis, multiple sclerosis, systemic lupus        erythematosus, ankylosing spondylitis, uveitis, polymyalgia        rheumatica, and type I diabetes, or a pharmaceutically        acceptable salt thereof.    -   [35a] The compound of [32a], wherein the disease is metabolic        disease, or a pharmaceutically acceptable salt thereof.    -   [36a] The compound of [35a], wherein the metabolic disease is        diabetes, or a pharmaceutically acceptable salt thereof.

The term “pharmaceutically acceptable salt” may be any salts withoutexcess toxicity known in the art.

In particular, it includes, for example, a salt with an inorganic acid,a salt with an organic acid, a salt with an inorganic base, and a saltwith an organic base. Various forms of pharmaceutically acceptable saltsare well known in the art, and are listed in the following references,for example.

-   (a) Berge et al., J. Pharm. Sci., 66, p 1-19 (1977),-   (b) Stahl et al., “Handbook of Pharmaceutical Salt: Properties,    Selection, and Use” (Wiley-VCH, Weinheim, Germany, 2002),-   (c) Paulekuhn et al., J. Med. Chem., 50, p 6665-6672 (2007)

The salt with an organic acid or inorganic acid includes a salt withacetic acid, adipic acid, alginic acid, 4-aminosalicylic acid,anhydromethylenecitric acid, benzoic acid, benzenesulfonic acid, calciumedetate, camphor acid, camphor-10-sulfonic acid, carbonic acid, citricacid, edetic acid, ethane-1,2-disulfonic acid, dodecylsulfonic acid,ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid,glucuronic acid, glucoheptonic acid, glycollylarsanilic acid,hexylresorcylic acid, hydrobromic acid, hydrochloric acid, hydrofluoricacid, hydroiodic acid, hydroxynaphthoic acid, 2-hydroxy-1-ethanesulfonicacid, lactic acid, lactobionic acid, malic acid, maleic acid, mandelicacid, methanesulfonic acid, methylsulfuric acid, methylnitric acid,methylenebis(salicylic acid), galactaric acid, naphthalene-2-sulfonicacid, 2-naphthoic acid, 1,5-naphthalenedisulfonic acid, nitric acid,oleic acid, oxalic acid, pamoic acid, pantothenic acid, pectic acid,phosphoric acid, picric acid, propionic acid, polygalacturonic acid,salicylic acid, stearic acid, succinic acid, sulfuric acid, tannic acid,tartaric acid, teoclic acid, thiocyanic acid, trifluoroacetic acid,p-toluenesulfonic acid, undecanoic acid, asparaginic acid or glutamicacid.

A preferable salt with an organic acid includes a salt with oxalic acid,maleic acid, citric acid, fumaric acid, lactic acid, malic acid,succinic acid, tartaric acid, acetic acid, trifluoroacetic acid, benzoicacid, glucuronic acid, oleic acid or pamoic acid. Alternatively, a saltwith methanesulfonic acid, benzenesulonic acid, p-toluenesulfonic acidor 2-hydroxy-1-ethanesulfonic acid is illustrated.

A preferable salt with an inorganic acid includes a salt withhydrochloric acid, nitric acid, sulfuric acid, phosphoric acid orhydrobromic acid.

The salt with an organic base includes a salt with arecoline, betaine,choline, clemizole, ethylenediamine, N-methylglucamine,N-benzylphenethylamine, tris(hydroxymethyl)methylamine, arginine orlysine.

A preferable salt with an organic base includes a salt withtris(hydroxymethyl)methylaminc, N-methylglucamine or lysine—The saltwith an inorganic base includes a salt with ammonium, aluminum, barium,bismuth, calcium, lithium, magnesium, potassium, sodium or zinc.

A preferable salt with an inorganic base includes a salt with sodium,potassium, calcium, magnesium or zinc.

According to known methods, each pharmaceutically acceptable salt may beobtained by reacting a compound of Formula [I] with an inorganic base,an organic base, an inorganic acid or an organic acid.

A preferable salt of a compound of Formula [I] includes a salt withsodium, potassium or calcium.

Another preferable salt of a compound of Formula [I] includes a saltwith sodium, potassium, L-lysine, tris(hydroxymethyl)methylamine,diethylamine, piperazine or dicyclohexylamine.

A compound of Formula [I] or a pharmaceutically acceptable salt thereofmay exist in its solvate.

The term “solvate” means a compound where a solvent molecule iscoordinated with a compound of Formula [I] or a pharmaceuticallyacceptable salt thereof, and includes a hydrate.

A pharmaceutically acceptable solvate is preferred as the solvate, andincludes, for example, a hydrate, an ethanolate, and adimethylsulfoxidate of a compound of Formula [I] or a pharmaceuticallyacceptable salt thereof.

In particular, it includes, for example, a hemihydrate, 1 hydrate, 2hydrate or 1 ethanolate of a compound of Formula [I], or a monohydrateof a sodium salt of a compound of Formula [I] or a 1/2 ethanolate ofdihydrochloride thereof.

According to known methods, the solvates may be obtained.

A compound of Formula [I] may exist as a tautomer. In that case, acompound of Formula [I] may exist as an individual tautomer or a mixtureof tautomers.

A compound of Formula [I] may have a carbon-carbon double bond. In thatcase, a compound of Formula [I] may exist as an E-isomer, a Z-isomer ora mixture of E- and Z-isomers.

A compound of Formula [I] may exist as a stereoisomer which should berecognized as a cis/trans isomer. In that case, a compound of Formula[I] may exist as a cis-isomer, a trans-isomer or a mixture of cis- andtrans-isomers.

A compound of Formula [I] may have one or more asymmetric carbonatom(s). in that case, a compound of Formula [I] may exist as a singleenantiomer, a single diastereomer, a mixture of enantiomers or a mixtureof diastereomers.

A compound of Formula [I] may exist as an atropisomer. In that case, acompound of Formula [I] may exist as an individual atropisomer or amixture of atropisomers.

A compound of Formula [I] may simultaneously have multiple structuralfeatures which can provide the above isomers. A compound of Formula [I]may also contain the above isomers in any ratios.

Formulae, chemical structures or chemical names without specifying astereochemistry herein include all the above isomers which may exist,unless otherwise specified.

Diastereomer mixtures may be isolated into each diastereomer by aconventional method such as chromatography or crystallization. Eachdiastereomer may be also prepared by using a starting material which isa single isomer in terms of stereochemistry or by a synthetic methodusing a stereoselective reaction.

A mixture of enantiomers may be isolated into each single enantiomer bya well known method in the art.

For example, a mixture of enantiomers may be reacted with asubstantially pure enantiomer which is known as a chiral auxiliary toform a mixture of diastereomers, which may be then isolated into adiastereomer with an enhanced isomeric ratio or a substantially puresingle diastereomer by a common method such as fractionatedcrystallization or chromatography. The added chiral auxiliary may beremoved from the isolated diastereomer by a cleavage reaction to give adesirable enantiomer.

A mixture of enantiomers may be also directly separated by a well knownchromatography in the art using a chiral stationary phase.

Alternatively, either of enantiomers may be also obtained by using asubstantially pure and optically active starting material or astereoselective synthesis (i.e., asymmetric induction) from a prochiralintermediate with a chiral auxiliary or asymmetric catalyst.

An absolute configuration may be determined by X-ray crystallographicanalysis of a crystalline product or intermediate. In that case, acrystalline product or intermediate which is induced by an agent havingan asymmetric center with a known configuration may be used if needed.

A compound of Formula [I] may be labeled with an isotope atom such as²H, ³H, ¹⁴C, and ³⁵S.

A compound of Formula [I] or a pharmaceutically acceptable salt thereofis preferably a substantially purified compound of Formula [I] orpharmaceutically acceptable salt thereof. A more preferable one is acompound of Formula [I] or a pharmaceutically acceptable salt thereofpurified in an 80% or more purity.

According to known methods in the art of pharmaceutical formulation, apharmaceutical composition in the present invention may be prepared byoptionally mixing a compound of Formula [I] or a pharmaceuticallyacceptable salt thereof with at least one or more pharmaceuticallyacceptable carrier(s) in any amount. A content of a compound of Formula[I] or a pharmaceutically acceptable salt thereof in the pharmaceuticalcomposition depends on dosage forms and doses, and is for example 0.1 to100% by weight of the composition.

A dosage form of a compound of Formula [I] or a pharmaceuticallyacceptable salt thereof includes an oral preparation such as a tablet, acapsule, a granule, a powder, a lozenge, a syrup, an emulsion, and asuspension or an parenteral preparation such as an external preparation,a suppository, an injection, an eye drop, a nasal preparation, and apulmonary preparation.

The term “pharmaceutically acceptable carrier” includes various commonorganic or inorganic carrier substances as a formulation material, andincludes excipients, disintegrants, binders, fluidizers, and lubricantsin a solid formulation, solvents, solubilizing agents, suspendingagents, tonicity agents, buffers, and soothing agents in a liquidformulation, and bases, emulsifying agents, wetting agents, stabilizers,stabilizing agents, dispersants, plasticizers, pH regulators, absorptionpromoters, gelators, preservatives, fillers, solubilizers, solubilizingagents, and suspending agents in a semisolid formulation.

A preserving agent, an antioxidant agent, a colorant or a sweeteningagent may be also optionally used as an additive.

The term “excipient” includes, for example, lactose, white soft sugar,D-mannitol, D-sorbitol, cornstarch, dextrin, microcrystalline cellulose,crystalline cellulose, carmellose, carmellose calcium, sodiumcarboxymethylstarch, low substituted hydroxypropylcellulose, and gumarabic.

The term “disintegrant” includes, for example, carmellose, carmellosecalcium, carmellose sodium, sodium carboxymethylstarch, croscarmellosesodium, crospovidone, low substituted hydroxypropylcellulose,hydroxypropylmethylcellulose, and crystalline cellulose.

The term “binder” includes, for example, hydroxypropylcellulose,hydroxypropylmethylcellulose, povidone, crystalline cellulose, whitesoft sugar, dextrin, starch, gelatin, carmellose sodium, and gum arabic.

The term “fluidizer” includes, for example, light anhydrous silicic acidand magnesium stearate.

The term “lubricant” includes, for example, magnesium stearate, calciumstearate, and talc.

The term “solvent” includes, for example, purified water, ethanol,propyleneglycol, macrogol, sesame oil, corn oil, and olive oil.

The term “solubilizing agent” includes, for example, propyleneglycol,D-mannitol, benzyl benzoate, ethanol, triethanolamine, sodium carbonate,and sodium citrate.

The term “suspending agent” includes, for example, benzalkoniumchloride, carmellose, hydroxypropylcellulose, propyleneglycol, povidone,methylcellulose, and glycerol monostearate.

The term “tonicity agent” includes, for example, glucose, D-sorbitol,sodium chloride, and D-mannitol.

The term “buffer” includes, for example, sodium hydrogen phosphate,sodium acetate, sodium carbonate, and sodium citrate.

The term “soothing agent” includes, for example, benzyl alcohol.

The term “base” includes, for example, water, animal or vegetable oilssuch as olive oil, corn oil, arachis oil, sesame oil, and castor oil,lower alcohols such as ethanol, propanol, propylene glycol, 1,3-butyleneglycol, and phenol, higher fatty acid and an ester thereof, waxes,higher alcohols, polyalcohols, hydrocarbons such as white petrolatum,liquid paraffin, and paraffin, hydrophilic petrolatum, purified lanolin,absorptive ointment, hydrous lanolin, hydrophilic ointment, starch,pullulan, gum arabic, tragacanth gum, gelatin, dextran, cellulosederivatives such as methylcellulose, carboxymethylcellulose,hydroxyethylcellulose, and hydroxypropylcellulose, synthetic polymerssuch as carboxyvinyl polymer, sodium polyacrylate, polyvinyl alcohol,and polyvinylpyrrolidone, propylene glycol, macrogol such as macrogol200 to 600, and a combination of two or more of them.

The term “preserving agent” includes, for example, ethylparahydroxybenzoate, chlorobutanol, benzyl alcohol, sodiumdehydroacetate, and sorbic acid.

The term “antioxidant agent” includes, for example, sodium sulfite andascorbic acid.

The term “colorant” includes, for example, food dye such as Food Red No.2 and No. 3, and Food Yellow No. 4 and No. 5, and ß-carotene.

The term “sweetening agent” includes, for example saccharin sodium,dipotassium glycyrrhizate, and aspartame.

A pharmaceutical composition in the present invention may beadministered to human as well as mammals other than human such as mice,rats, hamsters, guinea pigs, rabbits, cats, dogs, pigs, cattle, horses,sheep, and monkeys orally or parenterally such as locally, rectally,intravenously, intramuscularly, and subcutaneously. While a dose mayvary depending on subjects, diseases, symptoms, dosage forms, routes ofadministration and the like, for example when it is administered orallyto an adult patient the dose of a compound of Formula [I] as the activeingredient ranges generally from about 0.01 mg to about 1 g per day,which may be administered once to several times in a divided amount.

A compound of Formula [I] or a pharmaceutically acceptable salt thereofhas an inhibitory activity of Retinoid-related Orphan Receptor γ (RORγ),and is useful for treating or preventing various diseases or conditionswhich are expected to be improved by adjusting the RORγ inhibitoryactivity, e.g. autoimmune diseases such as rheumatoid arthritis,psoriasis, inflammatory bowel diseases such as Crohn's disease andulcerative colitis, multiple sclerosis, systemic lupus erythematosus(SLE), ankylosing spondylitis, uveitis, polymyalgia rheumatica, type Idiabetes, and graft versus host disease, allergic diseases such asasthma, dry eye, fibrosis such as lung fibrosis and primary biliarycirrhosis, and metabolic diseases such as diabetes.

The term “RORγ antagonist” means a compound having an ability whichinhibits the function of Retinoid-related Orphan Receptor γ (RORγ) tomake the activity thereof disappear or reduced.

To “inhibit RORγ” means that a function of RORγ is inhibited to make theactivity thereof disappear or reduced, which includes, for example, thefunction of RORγ is inhibited according to Test Example 1 describedhereafter. To “inhibit RORγ” preferably includes “inhibiting humanRORγ”. Inhibiting the function or disappearing or reducing the activitymay be preferably carried out during clinical indication in human.

The term “RORγ inhibitor” means any substance which inhibits RORγ, andmay be a low molecular compound, a nucleic acid, polypeptide, protein,antibody, vaccine and the like. A preferable “RORγ inhibitor” is “humanRORγ inhibitor”.

The term “treating” used herein includes improving symptoms, preventingsevere diseases, maintaining a remission, preventing exacerbation aswell as preventing relapse.

The term “preventing” used herein means suppressing pathogenesis ofsymptoms.

The term “autoimmune disease” means a generic name of diseases where animmune system overreacts to and attacks normal cells and tissues thereofto cause symptoms, and in particular, includes rheumatoid arthritis,psoriasis, inflammatory bowel diseases such as Crohn's disease andulcerative colitis, multiple sclerosis, systemic lupus erythematosus,Behcet's disease, sarcoidosis, Harada disease, ankylosing spondylitis,uveitis, polymyalgia rheumatics, type I diabetes, and graft versus hostdisease.

The term “allergic disease” means a disease derived from the conditionwhere an immune reaction excessively occurs against a certain antigen,and in particular, includes atopic dermatitis, allergic rhinitis such aspollen allergy, allergic conjunctivitis, allergic gastroenteritis,bronchial asthma, infantile asthma, food allergy, medication allergy,and hives.

The term “fibrosis” means a condition with increased fibroconnectivetissues, and in particular, includes lung fibrosis and primary biliarycirrhosis.

The term “metabolic disease” means a disease caused by abnormity ofmetabolic turnover or a disease which includes metabolic abnormality asan element that constitutes pathogenesis, and includes, for example,diabetes such as type I diabetes or type II diabetes.

Herein, the proposal of preferences and options in respect of differentfeatures of the compounds, methods, uses, and compositions comprises theproposal of combinations of those preferences and options for thedifferent features, insofar as they are combinable and compatible.

Methods for preparing a compound of Formula [I] or a pharmaceuticallyacceptable salt thereof are illustrated as below. A method for preparinga compound of Formula [I] or a pharmaceutically acceptable salt thereofis not however intended to be limited thereto.

Each compound obtained in each step may be isolated and/or purified byknown methods such as distillation, recrystallization, and columnchromatography, if necessary, but a reaction may optionally proceed to asequential step without isolation and purification.

In particular, a compound of Formula [I] may be prepared according tothe following Preparation Methods 1 to 5, for example:

Each definition of each substituent in schemes in each PreparationMethod is illustrative and is not limited thereto.

Preparation Method 1 A Method for Preparing Dihydropyrimidin-2-OneCompounds Via Claisen Reaction. (1)

In the formula,

-   -   P1 is for example C₁₋₄ alkyl;    -   R^(3q1) is for example —Y^(b)—CH₂OP² (in which P² is a        protective group such as trimethylsilyl (TMS) and        tert-butyldimethylsilyl (TBDMS)), C₁₋₆ alkyl optionally        substituted with hydroxy protected with one P², C₃₋₆ cycloalkyl        optionally substituted with the same or different one to three        substituent(s) selected from Group X^(b), 4-tetrahydropyranyl or        1-methanesulfonyl-3-azetidinyl;    -   Y^(b) is for example C₁₋₆ alkylene or C₃₋₆ cycloalkylene;    -   Group X^(b) is for example halogen or C₁₋₆ alkyl;    -   R^(5q) is for example —Y^(c)—COO—R^(q50) (in which R^(q50) is        C₁₋₄ alkyl), hydrogen, C₁₋₄ alkyl optionally substituted with        one C₁₋₃ alkoxy or C₃₋₆ cycloalkyl optionally substituted with        hydroxy-C₁₋₄ alkyl protected with one P2.    -   Yc is C₁₋₆, alkylene optionally substituted with hydroxy        protected with one P², CH₂—CH₂—O—CH₂ or        (CH₂)_(m)—Y^(c1)—(CH₂)_(w);    -   m is an integer of 0, 1 or 2;    -   w is an integer of 0, 1 or 2;    -   Y^(c1) is for example C₃₋₆ cycloalkylene optionally substituted        with one C₁₋₃ alkyl, phenylene, cross-linked C₅₋₈ cycloalkylene        or

-   -    and    -   the other symbols have the same meanings as defined in [01].

Step 1

A compound of Formula [Q-102] may be prepared from a compound of Formula[Q-101a] by a rearrangement reaction with diacetoxyiodobenzene (e.g. amethod described in Chem. Pharm. Bull., 1985, 33, 1097-1103).

A compound of Formula [Q-101a] may be prepared by Preparation Method 6described below.

Step 2

A compound of Formula [Q-103] may be prepared from a compound of Formula[Q-102] by hydrolysis with a base.

The base includes sodium hydroxide, potassium hydroxide, and lithiumhydroxide. A preferable base is sodium hydroxide.

A solvent includes methanol, ethanol, isopropanol, tetrahydrofuran, andwater, and may be used alone or by mixture of two or more of them. Apreferable solvent is a mixed solvent with ethanol and water.

A reaction temperature includes from room temperature to 100° C. Apreferable reaction temperature is room temperature.

Step 3

A compound of Formula [Q-105] may be prepared by a condensation reactionof a compound of Formula [Q-103] with a compound of Formula [Q-104].

A condensation agent includes aqueous carbodiimide (WSC·HCl:1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride),NN-dicyclohexylcarbodiimide (DCC), diphenylphosphoryl azide (DPPA), andcarbonyldiimidazole (CDI). For example, 1-hydroxy-1H-benzotriazolemonohydrate (HOBt·H₂O) or 4-dimethylaminopyridine (DMAP) may beoptionally added thereto. A preferable condensation agent is a mixtureof aqueous carbodiimide (WSC·HCl:1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride) and4-dimethylaminopyridine (DMAP).

A solvent includes toluene, dichloromethane, chloroform,tetrahydrofuran, dioxane, N,N-dimethylformamide, dimethylsulfoxide,acetonitrile, and acetone, and may be used alone or by mixture of two ormore of them. A preferable solvent is dichloromethane.

A reaction temperature includes from 0° C. to 100° C. A preferablereaction temperature is room temperature.

A compound of Formula [Q-104] may be prepared by Preparation Method 7-1described below.

Step 4

A compound of Formula [Q-106] may be prepared from a compound of Formula[Q-105] in the presence of a base and a chlorosilane compound by IrelandClaisen rearrangement reaction (e.g. a method described in Org. Lett.,2007, 9, 4431-4434).

The base includes lithium diisopropylamide (LDA), lithiumhexamethyldisilazide (LHMDS), and lithium 2,2,6,6-tetramethylpiperidide(LiTMP). A preferable base is lithium diisopropylamide (LDA).

The chlorosilane compound includes trimethylsilyl chloride andtert-butyldimethylsilyl chloride. A preferable chlorosilane compound istrimethylsilyl chloride.

Hexamethylphosphoric triamide (HMPA) or N,N′-dimethylpropyleneurea(DMPU) may be added as an additive.

A. solvent includes an ether type solvent such as diethyl ether,tetrahydrofuran, 1,2-dimethoxyethane. A preferable solvent istetrahydrofuran.

A reaction temperature includes from −78° C. to 80° C. A preferablereaction temperature is from −78° C. to room temperature.

Step 5

A compound of Formula [Q-107] may be prepared from a compound of Formula[Q-106] in the presence of a base by an azidation reaction followed byCurtius rearrangement reaction.

An azidation agent includes DPPA.

The base includes triethylamine and diisopropylethylamine. A preferablebase is triethylamine.

A solvent includes benzene, toluene, and xylene. A preferable solvent istoluene.

A reaction temperature includes from 0° C. to 140° C. A preferablereaction temperature is 110° C.

Step 6

A compound of Formula [Q-109] may be prepared from a compound of Formula[Q-107] and a compound of Formula [Q-108]. When a compound of Formula[Q-108] is hydrochloride, one or more equivalent(s) of a base such astriethylamine may be optionally added.

A solvent includes benzene, toluene, dichloromethane, chloroform,diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, ethyl acetate,N,N-dimethylformamide, dimethylsulfoxide, acetonitrile, and acetone, andmay be used alone or by mixture of two or more of them. A preferablesolvent is tetrahydrofuran.

A reaction temperature includes from 0° C. to 80° C. A preferablereaction temperature is from 0° C. to room temperature.

A compound of Formula [Q-108] may be prepared by Preparation Method 8-2described below.

Step 7

A compound of Formula [Q-110] may be prepared by an oxidative cleavagereaction of exo-olefin of a compound of Formula [Q-109], followed by acyclization reaction with an acid.

The oxidative cleavage reaction includes ozone oxidation by reductivetreatment. A reducing agent used in the oxidative cleavage reactionincludes dimethyl sulfide and triphenylphosphine. A preferable reducingagent is dimethyl sulfide.

The acid used in the cyclization reaction includes hydrochloric acid,acetic acid, hydrobromic acid, sulfuric acid, trifluoroacetic acid, andp-toluenesulfonic acid. A preferable acid is hydrochloric acid. The acidused in the cyclization reaction may be mixed with reactants from thebeginning or may be added to the reaction system after completion of theoxidative cleavage reaction.

A solvent includes methanol, ethanol, isopropyl alcohol, tert-butanol,dichloromethane, and chloroform, and may be used alone or by mixture oftwo or more of them. A preferable solvent is methanol, or a mixedsolvent of methanol with dichloromethane.

A reaction temperature includes from −100° C. to 80° C. A preferablereaction temperature is from −78° C. to room temperature.

Step 8

A compound of Formula [I] may be prepared from a compound of Formula[Q-110] by the following method. For example, a compound which R³ or R⁵has a hydroxyl group as a substituent in a compound of Formula [I] andthe hydroxyl group is protected with P² may be prepared by adeprotection reaction of P². The deprotection reaction may be carriedout from the compound obtained in the cyclization reaction by a methoddescribed in a reference (e.g. a method described in Peter G. M. Wuts(2007). Green's Protective Groups in Organic Synthesis Fourth Edition,Weinheim, Germany, Wiley-VCH, 165-215). Alternatively, the reaction maybe carried out under an acidic condition simultaneously with thecyclization reaction.

A compound which R³ has a carboxyl group as a substituent in a compoundof Formula [I] may be prepared by oxidizing a compound which R³1] has aprimary hydroxyl group as a substituent with Dess-Martin reagent to analdehyde (e.g. a method described in J. Org. Chem., 2000, 65,5498-5505), followed by an oxidation reaction of the aldehyde with2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO) and chlorous acid (e.g. amethod described in J. Org. Chem., 1999, 64, 2564-2566). Alternatively,a compound which R³ has a carboxyl group as a substituent may beprepared from a compound which R^(3q1) has an ester as a substituent bya hydrolysis reaction. The hydrolysis reaction may be carried out by amethod of the above Step 2 or a hydrolysis reaction with an acid such astrifluoroacetic acid.

A compound which R⁵ has a carboxyl group as a substituent in a compoundof Formula [I] may be prepared by an oxidation reaction of a hydroxylgroup or a hydrolysis reaction of an ester according to the PreparationMethod of the compound which R³ has a carboxyl group as a substituent.

For example, when R⁵ is “—Y^(c)—COO—R⁵⁰”, the compound may be preparedby the following hydrolysis reaction:

wherein R⁵⁰ is for example C₁₋₄ alkyl and the other symbols have thesame meanings as defined above.

For example when R³ is “—Y^(b)—COO—R³⁰”, the compound may be prepared bythe following hydrolysis reaction:

wherein R³⁰ is for example C₁₋₄ alkyl and the other symbols have thesame meanings as defined above.

For example, when R³ is “—Y^(b)—COO—R³⁰” in which R³⁰ is hydrogen, thecompound may be prepared by the following oxidation reaction:

wherein each symbol has the same meaning as defined above.

An example of Preparation Method 1 is as follows.

Preparation Method 2 A Method for Preparing Dihydropyrimidin-2-OneCompounds Via Claisen Reaction (2)

A compound of Formula [I] may be also prepared from a compound ofFormula [Q-201] prepared from a compound of Formula [Q-101 b] accordingto Preparation Method 1.

In the formula, Rq1 is for example bromo, iodo or benzyloxy, R^(3q) isfor example —Y^(b)—COO—R^(q30) (in which R^(q30) is C₁₋₄ alkyl), C₁₋₄alkyl optionally substituted with one C₁₋₃ alkoxy or C₃₋₆ cycloalkyloptionally substituted with hydroxy-C₁₋₄ alkyl protected with one P²,and the other symbols have the same meanings as defined above.

Preparation Method 2-1

A compound which R¹ is C₃₋₆ alkoxy, C₂₋₇ alkoxy substituted with onetrifluoromethyl or C₁₋₃ alkoxy substituted with one substituent selectedfrom Group X^(a) in Formula [I] may be prepared by the following method.

In the formula, Bn is benzyl, X^(q) is a leaving group such as halogenor a hydroxyl group, R¹² is a substituent (e.g. C₃₋₆ alkyl) whichcombines together with the oxygen atom on the benzene ring to form C₃₋₆alkoxy, C₂₋₇ alkoxy substituted with one trifluoromethyl or C₁₋₃ alkoxysubstituted with one substituent selected from Group X^(a), R¹ is forexample C₃₋₆ alkoxy or C₂₋₇ alkoxy substituted with one trifluoromethyl,and the other symbols have the same meanings as defined above.

Step 1

A compound of Formula [Q-202] may be prepared by deprotecting the benzylgroup of a compound of Formula [Q-201 a] according to a method describedin a reference (e.g. a method described in Peter G. M. Wuts (2007)Green's Protective Groups in Organic Synthesis Fourth Edition, Weinheim,Germany, Wiley-VCH, p102-120). For example, the benzyl group may beremoved by a reaction in the presence of Lewis acid in the step.

Lewis acid includes boron tribromide, boron trichloride, andtrimethylsilyl iodide. A preferable Lewis acid is boron tribromide.

A solvent includes benzene, toluene, dichloromethane, and chloroform. Apreferable solvent is dichloromethane.

A reaction temperature includes from −78° C. to 80° C. A preferablereaction temperature is −78° C.

Step 2

A compound of Formula [Q-204] may be prepared from a compound of Formula[Q-202] and a compound of Formula [Q-203].

When X^(q)1 is a leaving group such as halogen (alkylation reaction): Acompound of Formula [Q-202] may be coupled with a compound of Formula[Q-203] in the presence of a base to give a compound of Formula [Q-204].

The base includes sodium carbonate, potassium carbonate, cesiumcarbonate, and sodium hydrogencarbonate. A preferable base is cesiumcarbonate.

A solvent includes diethyl ether, tetrahydrofuran, dioxane,1,2-dimethoxyethane, benzene, toluene, methylene chloride, chloroform,ethyl acetate, acetone, N,N-dimethylformamide, and dimethylsulfoxide. Apreferable solvent is N,N-dimethylformamide.

A reaction temperature is from room temperature to 120° C. A preferablereaction temperature is 100° C.

When X^(q1) is a hydroxyl group (Mitsunobu reaction): A compound ofFormula [Q-202] may be subjected under Mitsunobu reaction with acompound of Formula [Q-203] in a solvent in the presence ofbis(2-methoxyethyl)azodicarboxylate and triphenylphosphine to give acompound of Formula [Q-204].

The solvent includes methylene chloride, chloroform, tetrahydrofuran,and toluene. A preferable solvent is tetrahydrofuran.

A reaction temperature includes from 0° C. to 100° C. A preferablereaction temperature is from room temperature to 60° C.

Step 3

A compound of Formula [I] may be prepared from a compound of Formula[Q-204] according to Preparation Method 1 Step 8.

An example of Preparation Method 2-1 is as follows.

Preparation Method 2-2

A compound which R¹ is, for example, C₄₋₈ alkyl or C₁₋₄ alkylsubstituted with one substituent selected from Group X^(a1) in Formula[I] (provided that R¹ is not C₃₋₆ alkoxy, C₂₋₇ alkoxy substituted withone trifluoromethyl or C₁₋₃ alkoxy substituted with one substituentselected from Group X^(a2)) may be prepared from a compound of Formula[Q-201b] by a cross coupling reaction or an insertion reaction of carbonmonoxide:

wherein R^(q)2 is for example bromo, iodo or trifluoromethanesulfonyloxy and the other symbols have the same meanings as definedabove.

The cross coupling reaction includes a method described in a reference(e.g. a method described in F. Diederich, P. J. Stang (1998).Metal-catalyzed Cross-coupling Reactions, Weinheim, Germany, Wiley-VCH),and the insertion reaction of carbon monoxide includes a methoddescribed in a reference (e.g. M. Schlosser (1994). Organometallics inSynthesis, Weinheim, Germany, Wiley-VCH).

In the formula, R¹ is for example C₄₋₈ alkyl or C₁₋₄ alkyl substitutedwith one substituent selected from Group X^(a1) (provided that R¹ is notC₃₋₆ alkoxy, C₂₋₇ alkoxy substituted with one trifluoromethyl or C₁₋₃alkoxy substituted with one substituent selected from Group X^(a2)), R¹⁰is for example C₂₋₆ alkyl, M¹ is boronic acid, boronic acid ester ortrifluoroborate salt, M² is zinc or zinc halide, and the other symbolshave the same meanings as defined above.

For compounds of Formula [Q-202a], Formula [Q-202b], and Formula [Q-2024a commercially available product (e.g. isobutylboronic acid,1-hexylboronic acid pinacol ester, potassium(3,3-dimethylbutyl)trifluoroborate, butylzinc bromide,cyclohexylacetylene) may be used or they may be for example preparedfrom a commercially available R¹-X^(qq) (e.g.1-chloro-3,3-dimethyl-butane, bromomethyl-cyclohexane; X^(qq) is chloro,bromo or iodo) according to known methods.

For example, a compound of Formula [Q-202a] may be prepared by thefollowing method.

A compound which M¹ is boronic acid may be prepared by preparingGrignard reagent from a commercially available compound such as R¹—Brand magnesium to react with trimethyl borate, triisopropyl borate, forexample.

A compound which M¹ is boronic acid ester may be prepared by reacting aboronic acid compound with pinacol.

A compound which M¹ is trifluoroborate salt may be prepared by reactinga boronic acid compound with potassium hydrogen fluoride.

For example, a compound of Formula [Q-202b] may be prepared from acommerically available compound such as R¹—I and zinc.

An activating agent of zinc includes iodine, trimethylsilyl chloride and1,2-dibromoethane, and may be used alone or by mixture of two or more ofthem. A preferable activating agent is trimethylsilyl chloride or1,2-dibromoethane.

A solvent includes tetrahydrofuran, N,N-dimethylformamide, andN,N-dimethylacetamide. A preferable solvent is tetrahydrofuran ordimethylacetamide.

A reaction temperature includes from room temperature to 80° C. Apreferable reaction temperature is room temperature.

For example, a commerically available product such as3,3-dimethyl-1-butyne, cyclohexylacetylene, and phenylacetylene may beused for a compound of Formula [Q-202c].

An alkynylene compound of Formula [I] obtained by Sonogashira reactionmay be converted into an alkyl compound by a catalytic hydrogen additionreaction with a catalyst such as palladium on carbon, platinum oncarbon, and rhodium-alumina.

In the insertion reaction of carbon monoxide, a compound of Formula[Q-201b] may be reacted in an alcohol solvent such as ethanol to convertinto an ester corresponding to the alcohol.

In a compound of Formula [I], a compound which R³ or R⁵ has a hydroxylgroup as a substituent, a compound which R³ has a carboxyl group as asubstituent or a compound which R⁵ has a carboxyl group as a substituentmay be prepared according to Preparation Method 2-1 Step 3.

An example of Preparation Method 2-2 is as follows.

Preparation Method 3 A Method for Preparing Dihydropyrimidin-2-OneCompounds Via Biginelli Reaction

A compound which R⁶ is hydrogen in a compound of Formula [I] may beprepared by Bintelli reaction.

In the formula, R⁶ is hydrogen and each symbol has the same meaning asdefined above.

Step 1

A compound of Formula [I] may be prepared by reacting a compound ofFormula [Q-301], a compound of Formula [Q-302], and a compound ofFormula [Q-303] in the presence of an acid.

The acid includes hydrochloric acid, acetic acid, trimethylchlorosilane,and p-toluenesulfonic acid. A preferable acid is trimethylchlorosilane.

A solvent includes toluene, dichloromethane, chloroform,tetrahydrofuran, dioxane, N,N-dimethylformamide, dimethylsulfoxide,acetonitrile, and acetone, and may be used alone or by mixture of two ormore of them. A preferable solvent in the reaction is a mixed solvent ofacetonitrile and N,N-dimethylformamide.

A reaction temperature includes from 0° C. to 140° C. A preferablereaction temperature is from room temperature to 120° C.

A compound of Formula [Q-301] may be prepared by Preparation Method 6described below.

A compound of Formula [Q-302] may be prepared by Preparation Method 7-2described below.

A compound of Formula [Q-303] may be prepared by Preparation Method 8-3described below.

A compound which R³ or R⁵ has a hydroxyl group as a substituent, acompound which R³ has a carboxyl group as a substituent or a compoundwhich R⁵ has a carboxyl group as a substituent in a compound of Formula[I] may be prepared according to Preparation Method 2-1 Step 3.

Preparation Method 4 A Method for Preparing Dihydropyrimidin-2-OneCompounds Using Optically Active Sulfinyl Amide (1)

A compound of Formula [IV-D] wherein R⁴ is hydrogen in a compound ofFormula [I]:

may be prepared under an asymmetric synthesis with optically activesulfinyl amide.

In the formula, R^(3q2) is for example —Y^(b)—CH₂OP³ (in which P³ is aprotective group such as tert-butyldiphenylsilyl (TBDPS) and benzyl),C₁₋₆ alkyl optionally substituted with a hydroxyl group protected withone P3, C₃₋₆ cycloalkyl optionally substituted with the same ordifferent one to three substituent(s) selected from Group X^(b),4-tetrahydropyranyl or 1-methanesulfonyl-3-azetidinyl; R⁶ is for exampletert-butyl; and the other symbols have the same meanings as definedabove.

Step 1

A compound of Formula [Q-403] may be prepared by reacting a compound ofFormula [Q-401a] and a compound of Formula [Q-402] in the presence ofLewis acid according to a method described in a reference (e.g. a methoddescribed in G. K. Dana; J. A. Ellman, J. Org. Chem. 2010, 75,6283-6285).

An illustrative example of a compound of Formula [Q-402] includes thefollowing compound.

Lewis acid includes Lewis acid such as tetraalkyl orthotitanate. Apreferable Lewis acid is tetraethyl orthotitanate.

A solvent includes benzene, toluene, dichloromethane, chloroform,tetrahydrofuran, dioxane, 1,2-dimethoxyethane, and cyclopentylmethylether. A preferable solvent is cyclopentylmethyl ether.

A reaction temperature includes from room temperature to 120° C. Apreferable reaction temperature is 110° C.

A commercially available product may be used for a compound of Formula[Q-401 a] or it may be prepared by known methods or Preparation Method6.

Step 2

A compound of Formula [Q-405] may be prepared by reacting a compound ofFormula [Q-403] and a compound of Formula [Q-404] in the presence of abase according to a method described in a reference (e.g. a methoddescribed in T. P. Tang; J. A. Ellman, J. Org. Chem. 2002, 67,7819-7832).

The base includes lithium diisopropylamide (LDA), lithiumhexamethyldisilazide (LHMDS), and lithium 2,2,6,6-tetramethylpiperidide(LiTMP). A preferable base is lithium diisopropylamide (LDA) or lithiumhexamethyldisilazide (LHMDS).

A solvent includes benzene, toluene, xylene, hexane, tetrahydrofuran,dioxane, and 1,2-dimethoxyethane, and may be used alone or by mixture oftwo or more of them. A preferable solvent is tetrahydrofuran.

A reaction temperature includes from −78° C. to room temperature. Apreferable reaction temperature is from −78° C. to 0° C.

To improve diastereoselectivity, an additive such as titanium (IV)chlorotriisopropoxy may be also added.

An equivalent amount of the base includes from 1 to 3 equivalent(s). Apreferable amount is 2.1 equivalents.

A commercially available product may be used for a compound of Formula[Q-404] or it may be prepared by known methods or Preparation Method 6.

Step 3

A compound of Formula [Q-406] may be prepared by reacting a compound ofFormula [Q-405] with a reducing agent.

The reducing agent includes diisobutylaluminum hydride, lithium aluminumhydride, and lithium borohydride. A preferable reducing agent isdiisobutylaluminum hydride.

A solvent includes toluene, dichloromethane, diethyl ether, andtetrahydrofuran. A preferable solvent is toluene—A reaction temperatureincludes from −78° C. to room temperature. A preferable reactiontemperature is from −78° C. to 0° C.

Step 4

A compound of Formula [Q-407] may be prepared by hydrolyze a compound ofFormula [Q-406] under an acidic condition.

The acid includes hydrochloric acid, hydrobromic acid, sulfuric acid,trifluoroacetic acid, and p-toluenesulfonic acid. A preferable acid ishydrochloric acid.

A solvent includes tetrahydrofuran, methanol, ethanol, and isopropylalcohol, and may be used alone or by mixture of two or more of them. Apreferable solvent is methanol.

A reaction temperature includes from 0° C. to 60° C. A preferablereaction temperature is from 0° C. to room temperature.

Step 5

A compound of Formula [Q-409] may be prepared from a compound of Formula[Q-407] and a compound of Formula [Q-408].

A solvent includes benzene, toluene, dichloromethane, chloroform,diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, ethyl acetate,N,N-dimethylformamide, dimethylsulfoxide, acetonitrile, and acetone, andmay be used alone or by mixture of two or more of them. A preferablesolvent is tetrahydrofuran.

A reaction temperature includes from 0° C. to 80° C. A preferablereaction temperature is from 0° C. to room temperature.

Step 6

A compound of Formula [Q-410] may be prepared by an oxidation reactionof a compound of Formula [Q-409], followed by a cyclization reaction.

The oxidizing agent includes 2-azaadamantane-N-oxyl (AZADO),2,2,6,6-tetramethyl-1-piperidinyloxy radical (TEMPO), and Dess-Martinreagent (DMP). Diacetoxyiodobenzene or sodium hydrochlorite, forexample, may be optionally added as a co-oxidizing agent. A preferableoxidizing agent in the reaction is a mixture of2,2,6,6-tetramethyl-1-piperidinyloxy radical (TEMPO) anddiacetoxyiodobenzene.

The acid in the cyclization reaction includes hydrochloric acid,trifluoroacetic acid, and p-toluenesulfonic acid. A preferable acid istrifluoroacetic acid.

A solvent includes tert-butanol, benzene, toluene, dichloromethane,chloroform, ethyl acetate, and acetonitrile. A preferable solvent in thereaction is dichloromethane or chloroform.

A reaction temperature includes from 0° C. to 80° C. A preferablereaction temperature is from 0° C. to room temperature.

Step 7

A compound which R³ or R⁵ has a hydroxyl group as a substituent, acompound which R³ has a carboxyl group as a substituent or a compoundwhich R⁵ has a carboxyl group as a substituent in a compound of Formula[IV-D] may be prepared according to Preparation Method 1 Step 8.

The following compound of Formula [E-IV-D] may be prepared using anenantiomer (i.e., a compound of Formula [E-Q-402]) of a compound ofFormula [Q-402] according to Preparation Method 4.

Preparation Method 5 A Method for Preparing Dihydropyrimidin-2-OneCompounds Using Optically Active Sulfinyl Amide (2) Alternative Methodfor Preparing a Compound of Formula [IV-D]

A compound of Formula [Q-501] may be prepared from a compound of Formula[Q-401b] and a compound of Formula [Q-402] according to PreparationMethod 4. A compound of Formula [IV-D] may be prepared from a compoundof Formula [Q-501] according to the following Preparation. Method 5-1 or5-2.

In the formula, each symbol has the same meaning as defined above.

Preparation Method 5-1

When R^(q)1 is for example a hydroxyl group in a compound of Formula[Q-501]:

For example, a compound of Formula [Q-503] which R¹ is C₃₋₆ alkoxy, C₂₋₇alkoxy substituted with one trifluoromethyl or C₁₋₃ alkoxy substitutedwith one substituent selected from Group X^(a2) in Formula [IV-D] may beprepared by the following method.

In the formula, R¹ is C₃_s alkoxy, C₂₋₇ alkoxy substituted with onetrifluoromethyl or C₁₋₃ alkoxy substituted with one substituent selectedfrom Group X^(a2), and the other symbols have the same meanings asdefined above.

A compound of Formula [Q-501a] may be prepared from a compound whichR^(q)1 is a benzyl ether group in a compound of Formula [Q-401b]according to Preparation Method 4.

A compound of Formula [Q-503] may be prepared from a compound of Formula[Q-501a] according to Preparation Method 2-1.

Preparation Method 5-2

When R^(q)1 is for example bromo, iodo or trifluoromethanesulfonyloxygroup in a compound of Formula [Q-501]:

A compound which R¹ is a substituent such as C₄₋₈ alkyl and C₁₋₄ alkylsubstituted with one substituent selected from Group X^(a1) in Formula[IV-D] (provided that R¹ is not C₃₋₆ alkoxy, C₂₋₇ alkoxy substitutedwith one trifluoromethyl or C₁₋₃ alkoxy substituted with one substituentselected from Group X^(a2)) may be prepared from a compound of thefollowing Formula [Q-501b] by a cross coupling reaction or an insertionreaction of carbon monoxide.

In the formula, each symbol has the same meaning as defined above.

-   -   [Q-501b]

In the formula, each symbol has the same meaning as defined above.

A compound of Formula [IV-D] may be prepared from a compound of Formula[Q-501b] according to Preparation Method 2-2.

In particular, Preparation Method 5-2 (Suzuki coupling) is for exampleas follows. A compound of Formula [R¹-M¹] may be synthesized by a commonprocedure.

In the formula, GrubbsCat.2nd means a second-generation Grubbs catalyst,(1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinyliene)dichloro(phenylmethylene)(tricyclohexylphosphine)-ruthenium,and the other symbols have the same meanings as defined above.

Preparation Method 5-3

When R^(q) is bromo in a compound of Formula [Q-501] (i.e., a compoundof Formula [Q-504]):

A compound which R¹ is C₃₋₆ alkylsulfanyl, C₃₋₆ alkylsulfinyl, C₃₋₆alkylsulfonyl, C₃₋₆ cycloalkylsulfanyl, C₃₋₆ cycloalkylsulfinyl or C₃₋₆cycloalkylsulfonyl in Formula [IV-D] may be prepared by the followingmethod.

-   -   In the formula,    -   R^(1s) is C₃₋₆ alkyl or C₃₋₆ cycloalkyl,    -   R¹ is C₃₋₆ alkylsulfanyl or C₃₋₆ cycloalkylsulfanyl,    -   R^(5q) is —Y^(c)—COOR^(q50) wherein Y^(c) is C₁₋₆ alkylene        optionally substituted with one hydroxy and R^(q50) is hydrogen        or C₁₋₄ alkyl,    -   R⁵ is —Y—COOH,    -   R⁶ is methyl, and the other symbols have the same meanings as        defined above.

A compound of Formula [Q-504] may be prepared from a compound of Formula[Q-401c] using Preparation Method 5.

Step 1

A compound of Formula [Q-506] may be prepared by a coupling reaction ofa compound of Formula [Q-504] and a compound of Formula [Q-505]according to a method described in a literature such as a methoddescribed in Org. Lett. 2004, 6, 4587-4590, for example.

Step 2

A compound of Formula [IV-D] may be prepared from a compound of Formula[Q-506] according to Preparation Method 1 Step 8.

For example, an illustrative example of Preparation Method 5-3 includesthe following reactions:

Preparation Method 5-3-A

-   -   In the formula,    -   R^(1s) is C₃₋₆ alkyl or C₃₋₆ cycloalkyl,    -   R¹ is C₃₋₆ alkylsulfinyl or C₃₋₆ cycloalkylsulfinyl,    -   R^(5q) is —Y^(c)—COOR^(q50) wherein Y^(c) is C₁₋₆ alkylene        optionally substituted with one hydroxy and R^(q50) is hydrogen        or C₁₋₄ alkyl,    -   R⁵ is —Y^(c)—COOH,    -   R⁶ is methyl, and the other symbols have the same meanings as        defined above.

Step 1

A compound of Formula [Q-507] may be prepared by an oxidation reactionof sulfide of a compound of Formula [Q-506].

An oxidizing agent includes hydrogen peroxide, peracetic acid.hydroperoxide, permanganate, meta-chloroperbenzoic acid, and sodiumhypochlorite. A preferable oxidizing agent is meta-chloroperbenzoicacid.

A solvent includes benzene, dichloromethane, acetonitrile, and water,and may be used alone or by mixture of two or more of them. A preferablesolvent is dichloromethane.

A reaction temperature includes from −78° C. to room temperature. Apreferable reaction temperature is −78° C.

Step 2

A compound of Formula [IV-D] may be prepared from a compound of Formula[Q-507] according to Preparation Method 1 Step 8.

Preparation Method 5-3-B

-   -   In the formula,    -   R^(1s) is C₃₋₆ alkyl or C₃₋₆ cycloalkyl,    -   R¹ is C₃₋₆ alkylsulfonyl or C₃₋₆ cycloalkylsulfonyl,    -   R^(5q) is —Y^(c)—COOR^(q50) wherein Y^(c) is C₁₋₆ alkylene        optionally substituted with one hydroxy and R^(q50) is hydrogen        or C₁₋₄ alkyl,    -   R⁵ is —Y^(c)—COOH,    -   R⁶ is methyl, and the other symbols have the same meanings as        defined above.

Step 1

A compound of Formula [Q-508] may be prepared by an oxidation reactionof sulfide of a compound of Formula [Q-506].

An oxidizing agent includes oxone, meta-chloroperbenzoic acid, andpotassium permanganate. A preferable oxidizing agent ismeta-chloroperbenzoic acid.

A solvent includes benzene, dichloromethane, acetonitrile, and water,and may be used alone or by mixture of two or more of them. A preferablesolvent is dichloromethane.

A reaction temperature includes from −78° C. to room temperature. Apreferable reaction temperature is room temperature.

Step 2

A compound of Formula [IV-D] may be prepared from a compound of Formula[Q-508] according to Preparation Method 1 Step 8.

Preparation Method 5-4

Preparation Method of Dihydropyrimidin-2-One Compounds Using OpticallyActive Sulfinylamide (4) (i.e., an Alternative Method for Preparing aCompound of Formula [IV-D] Using p-Nitrophenyl Chloroformate)

A compound of Formula [Q-520] may be prepared from a compound of Formula[Q-401a] according to Preparation Method 4. A compound of Formula [IV-D]may be prepared from a compound of Formula [Q-520] using cross-couplingreaction.

In the formula, R^(3q3) is —Y^(b)—COOR^(q30) wherein Y^(b) is phenyl andR^(q30) is hydrogen or C₁₋₄ alkyl, R⁶ is methyl, and the other symbolshave the same meanings as defined above.

Step 1

The reaction is carried out in a similar way to Preparation Method 4Step 1.

Step 2

A compound of Formula [Q-511] may be prepared by reacting a compound ofFormula [Q-403] with a compound of Formula [Q-510] under a basiccondition.

A base includes lithium diisopropylamide (LDA), lithiumhexamethyldisilazide (LHMDS), and lithium 2,2,6,6-tetramethylpiperidide(LiTMP). A preferable base is lithium diisopropylamide (LDA) or lithiumhexamethyldisilazide (LHMDS).

A solvent includes benzene, toluene, xylene, hexane, tetrahydrofuran,dioxane, and 1,2-dimethoxyethane, and may be used alone or by mixture oftwo or more of them. A preferable solvent is tetrahydrofuran.

A reaction temperature includes from −78° C. to room temperature. Apreferable reaction temperature is from −78° C. to 0° C.

To improve a diastereoselectivity, an additive such aschlorotriisopropoxy titanium (IV) may be further added.

An equivalent amount of a base includes from 1 to 3 equivalentamount(s). A preferable equivalent amount is 2.1 equivalent amounts.

As a compound of Formula [Q-510], a commercially available product suchas 3-hydroxy-propionic acid methyl ester, 3-hydroxy-propionic acid ethylester, and 3-hydroxy-propionic acid t-butyl ester may be used.

Step 3

A compound of Formula [Q-512] may be prepared by hydrolyzing a compoundof Formula [Q-511] under an acidic condition.

An acid includes hydrochloric acid, hydrobromic acid, sulfuric acid,trifluoroacetic acid, and p-toluenesulfonic acid. A preferable acid ishydrochloric acid.

A solvent includes tetrahydrofuran, methanol, ethanol, and isopropylalcohol, and may be used alone or by mixture of two or more of them. Apreferable solvent is methanol.

A reaction temperature includes from 0° C. to 60° C. A preferablereaction temperature is from 0° C. to room temperature.

Step 4

A compound of Formula [Q-513] may be prepared by protecting a compoundof Formula [Q-512] with tert-butyldiphenylsilyl (TBDPS) according to amethod described in a literature (e.g. a method described in Peter G. M.Wuts (2007). Green's Protective Groups in Organic Synthesis FourthEdition, Weinheim, Germany, Wiley-VCH, 141-144).

Step 5

A compound of Formula [Q-514] may be prepared by reacting a compound ofFormula [Q-513] with p-nitrophenyl chloroformate under a basiccondition.

A base includes triethylamine, diisopropylethylamine, pyridine,N-methylmorpholine, and potassium carbonate. A preferable base istriethylamine.

A solvent includes chloroform, dichloromethane, toluene,tetrahydrofuran, and acetonitrile. A preferable solvent is chloroform.

A reaction temperature includes from 0° C. to 85° C. A preferablereaction temperature is 0° C.

Step 6

A compound of Formula [Q-516] may be prepared by reacting a compound ofFormula [Q-514] with a compound of Formula [Q-515] under a basiccondition.

A base includes triethylamine and diisopropylethylamine. A preferablebase is triethylamine.

A solvent includes chloroform, dichloromethane, and tetrahydrofuran. Apreferable solvent is chloroform.

A reaction temperature includes from room temperature to 60° C. Apreferable reaction temperature is 60° C.

Step 7

A compound of Formula [Q-517] may be prepared by deprotectingtert-butyldiphenylsilyl (TBDPS) of a compound of Formula [Q-516]according to a method described in a literature (e.g. a method describedin Peter G. M. Wuts (2007). Green's Protective Groups in OrganicSynthesis Fourth Edition, Weinheim, Germany, Wiley-VCH, 142-143).

Step 8

A compound of Formula [Q-518] may be prepared from a compound of Formula[Q-517] according to Preparation Method 4 Step 6.

Step 9

A compound of Formula [Q-519] may be prepared by deprotecting tert-butylester from a compound of Formula [Q-518] wherein P1 is for exampletert-butyl according to a method described in a literature (e.g. amethod described in Peter G. M. Wuts. Protective Groups in OrganicSynthesis Third Edition, Wiley-Interscience, 406-407).

Step 10

A compound of Formula [Q-520] may be prepared by brominating a compoundof Formula [Q-519] according to a method described in a literature (e.g.a method described in A. J. Zych; H. Wang; S. A. Sakwa, TetrahedronLett. 2010, 51, 5103-5105).

Step 11

A compound of Formula [Q-522] may be prepared from a compound of Formula[Q-520] and a compound of Formula [Q-521] according to PreparationMethod 2-2 (including cross-coupling).

Step 12

A compound of Formula [IV-D] may be prepared for example by hydrolyzinga compound of Formula [Q-522].

In Preparation Method 5-4, Step 11 (coupling reaction) and Step 12(hydrolysis reaction) are illustrated as follows.

In the formula, R⁶ is methyl, and the other symbols have the samemeanings as defined above.

Preparation Method 5-5 Preparation Method of Dihydropyrimidin-2-OneCompounds Using Optically Active Sulfinylamide (5) (i.e., an AlternativeMethod for Preparing a Compound of Formula [IV-D])

A compound of Formula [Q-536] may be prepared from a compound of Formula[Q-401 a] using Preparation Methods 4 and 5-4. A compound of Formula[IV-D] may be prepared from a compound of Formula [Q-536] by acyclization reaction under a basic condition, a reduction reaction usingSchwartz's reagent, an oxidation reaction using Dess-Martin reagent intoan aldehyde compound, followed by Pinnic Oxidation into a carboxylicacid compound.

In the formula, Y^(b) is C₃₋₆ cycloalkylene, R³ is —Y^(b)—COOH, R⁶ ismethyl; and the other symbols have the same meanings as defined above.

Protective groups in the formula may be optionally changed. For example,TBDMS (tert-butyldimethylsilyl) may be replaced with TBDPS(tert-butyldiphenylsilyl), and MOM (methoxymethyl) may be replaced withmethyl.

Step 1

A compound of Formula [Q-403] may be prepared from a compound of Formula[Q-401a] according to Preparation Method 4 Step 1.

Step 2

A compound of Formula [Q-531] may be prepared from a compound of Formula[Q-403] and a compound of Formula [Q-530] according to PreparationMethod 4 Step 2. A compound of Formula [Q-530] may be commerciallyavailable or synthesized by a method described in a literature (e.g. amethod described in WO 2009/019174).

Step 3

A compound of Formula [Q-403] may be prepared from a compound of Formula[Q-401a] according to Preparation Method 4 Step 4.

Step 4

A compound of Formula [Q-533] may be prepared by protecting a compoundof Formula [Q-532] with tert-butyldimethylsilyl (TBDMS) according to amethod described in a literature (e.g. a method described in Peter G. M.Wuts. Protective Groups in Organic Synthesis Third Edition,Wiley-Interscience, 127-131).

Step 5

A compound of Formula [Q-534] may be prepared from a compound of Formula[Q-533] according to Preparation Method 5 Step 5.

Step 6

A compound of Formula [Q-536] may be prepared from a compound of Formula[Q-534] and a compound of Formula [Q-535] according to PreparationMethod 5 Step 6.

Step 7

A compound of Formula [Q-537] may be prepared by cyclizing a compound ofFormula [Q-536] according to a method described in a literature (e.g. amethod described in R. Patino-Molina; 1. Cubero-Lajo; M. J. P. Vega; M.T. Garcia-Lopez, Tetrahedron Lett. 2007, 48, 3615-3616).

Step 8

A compound of Formula [Q-538[may be prepared by reducing a compound ofFormula [Q-537] with Schwartz's reagent according to a method describedin for example S. R. Dandepally; R. Elgoummadi; A. L. Williams,Tetrahedron Lett. 2013, 54, 925-928.

Step 9

A compound of Formula [Q-539] may be prepared by oxidizing a compound ofFormula [Q-538] with Dess-Martin reagent (e.g. a method described in E.Vedejs; D. W. Piotrowski; F. C. Tucci, J. Org. Chem. 20009 65,5498-5505).

Step 10

A compound of Formula [IV-D] may be prepared from a compound of Formula[Q-539] by Pinnick oxidation (e.g. a method described in G. A. Kraus; B.Roth, J. Org. Chem. 1980, 45, 4825-4830).

Preparation Method 5-5 is illustrated in the following reactions whenchemical name: (3-methoxymethoxymethyl-cyclobutyl)-acetic acid methylester is used as a compound of Formula [Q-530] and chemical name:3,3-difluoro-cyclobutylamine is used as a compound of Formula [Q-535].

In the formula, R⁶ is methyl, and the other symbols have the samemeanings as defined above.

Preparation Method 6 Methods for Preparing Starting Materials ofPreparation Methods 1 to 5 Preparation Method 6-1

A compound of Formula [Q-101b] Formula [Q-301a] or [Q-401b] which is astarting material of Preparation Method 2 or 5 is represented by thefollowing general formula:

wherein U¹ is formyl, acetyl or ethylcarbonyl (which means eachembodiment of —(C═O)—H, —(C═O)—R⁶ or —(C═O)—CH₂—R⁶ wherein R⁶ ishydrogen or methyl, respectively), and the other symbols have the samemeanings as defined above. A commercially available product (e.g.4-bromo-3-chloro-benzaldehyde, 1-(4-bromo-3-chloro-phenyl)-ethanone,1-(4-bromo-3-chloro-phenyl)-propan-1-one) may be used for the compoundor it may be prepared by known methods.

For example, it may be prepared by the following method.

In the formula, each symbol has the same meaning as defined above.

Step 1

A compound of Formula [Q-602] may be prepared by a condensation reactionof a compound of Formula [Q-601] with N,O-dimethylhydroxylamine orN,O-dimethylhydroxylamine hydrochloride.

The condensation agent includes aqueous carbodiimide (WSC·HCl:1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride),N,N′-dicyclohexylcarbodiimide (DCC), diphenylphosphoryl azide (DPPA),and carbonyldiimidazole (CDI). For example, 1-hydroxy-1H-benzotriazolemonohydrate (HOBt·H₂O) or 4-dimethylaminopyridine (DMAP) may beoptionally added. A preferable condensation agent in the step is amixture of aqueous carbodiimide (WSC·HCl:1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride) and1-hydroxy-1H-benzotriazole monohydrate (HOBt·H₂O).

A solvent includes toluene, dichloromethane, chloroform,tetrahydrofuran, dioxane, N,N-dimethylformamide, dimethylsulfoxide,acetonitrile, and acetone, and may be used alone or by mixture of two ormore of them. A preferable solvent in the reaction isN,N-dimethylformamide or acetonitrile.

Step 2

A compound of Formula [Q-101b] or Formula [Q-401b] may be prepared byreacting a compound of Formula [Q-602] with Grignard reagent such asMeMgX and EtMgX (wherein X is chloro or bromo).

A solvent includes an ether solvent such as diethyl ether,tetrahydrofuran (THF), and 1,2-dimethoxyethane (DME). A preferablesolvent is THF.

A compound of Formula [Q-301a] may be prepared by reacting a compound ofFormula [Q-602] with a reducing agent such as diisobutylaluminum hydride(DIBAL-H).

For example, a compound which U¹ is formyl or ketone may be alsoprepared from a commercially available compound such as2,2-dimethyl-indane-5-carboxylic acid in place of a compound of Formula[Q-601] by the above Steps 1 and 2.

In the formula, U¹ is formyl, acetyl or ethylcarbonyl and each symbolhas the same meaning as defined above.

Preparation Method 6-2 Preparation Method 6-2A Synthesis of the StartingMaterial in Preparation Method 1, 3 or 4

A compound of Formula [Q-101a], a starting material of PreparationMethod 1, a compound of Formula [Q-301], a starting material ofPreparation Method 3, and a compound of Formula [Q-401a], a startingmaterial of Preparation Method 4, are represented by the followinggeneral formula:

wherein each symbol has the same meaning as defined above.

The above compound may be for example prepared according to thefollowing method.

In the formula, each symbol has the same meaning as defined above.

Step 1 to Step 2

For example, a compound of Formula [Q-101a], Formula [Q-301] or Formula[Q-401a] wherein R¹ is C₃₋₆ alkoxy, C₂₋₇ alkoxy substituted with onetrifluoromethyl or C₁₋₃ alkoxy substituted with one substituent selectedfrom Group X^(a2) may be prepared from a compound of Formula [Q-101b1]or Formula [Q-401b1] via a compound of Formula [Q-603].

Each Step may be carried out according to Preparation Method 2-1 Step 1(a deprotection reaction of benzyl group) and Step 2 (a reaction with acompound of Formula [Q-203]).

Step 3

For example, a compound of Formula [Q-101a], Formula [Q-301] or Formula[Q-401a] wherein R¹ is C₄₋₈ alkyl or C₁₋₄ alkyl substituted with onesubstituent selected from Group X^(a1) but R¹ is not C₃₋₆ alkoxy, C₂₋₇alkoxy substituted with one trifluoromethyl or C₁₋₃ alkoxy substitutedwith one substituent selected from Group X^(a2) may be prepared from acompound of Formula [Q-101b2] or Formula [Q-401b2].

In the step, a cross-coupling reaction using palladium (including Suzukireaction) may be carried out according to Preparation Method 2-2.

Preparation Method 6-2B

In the formula, U is acetyl or ethylcarbonyl, and each symbol has thesame meaning as defined above.

Step 1

A compound of Formula [Q-102b] may be prepared from2-(3-chloro-4-trifluoromethanesulfonyloxy-phenyl)-propionic-acid-methyl-esterprepared from known2-(3-chloro-4-hydroxy-phenyl)-propionic-acid-methyl-ester or a compoundof the following Formula [Q-101b2] according to Preparation Method 1Step 1.

Step 2

A compound of Formula [Q-102] may be prepared from a compound of Formula[Q-102b] according to Preparation Method 2-2.

Preparation Method 6-3

A compound of Formula [Q-101a], [Q-301] or [Q-401a] which is a startingmaterial of Preparation Method 1, 3 or 4:

wherein each symbol has the same meaning as defined above may beprepared by the following method, for example.

In the formula, R¹¹ is for example C₂₋₄ alkyl, and the other symbolshave the same meanings as defined above.

Step 1

As a compound of Formula [Q-604], a commercially available compound suchas (4-bromo-3-chloro-phenyl)-methanol,(4-bromo-3,5-dimethyl-phenyl)-methanol, and(4-bromo-2-methoxide-phenyl)-methanol may be used. A compound of Formula[Q-605] may be prepared by reacting a compound of Formula [Q-604] with acommercially available compound such as R¹¹—Br in the presence of a basesuch as sodium hydride.

A solvent includes N,N-dimethylformamide.

A compound of Formula [Q-605] wherein R¹¹ is tert-butyl may be preparedby reacting a compound of Formula [Q-604] with di-tert-butyl dicarbonatein the presence of magnesium perchlorate (e.g. a method described inOrg. Lett., 2005, 7, 427-430).

Step 2

A compound of Formula [Q-606] may be prepared from a compound of Formula[Q-605] according to an insertion reaction of carbon monoxide inPreparation Method 2-2.

A solvent includes a mixed solvent of toluene and water.

The corresponding formyl, acetyl or ethylcarbonyl compound of Formula[Q-101a], [Q-301] or [Q-401 a] may be prepared from a compound ofFormula [Q-606] according to Preparation Method 6-1.

Preparation Method 6-4

A compound of Formula [Q-101a], [Q-301] or [Q-401a] which is a startingmaterial of Preparation Method 1, 3 or 4:

wherein each symbol has the same meaning as defined abovemay be also prepared by a formation reaction of carbon-carbon bond of acompound of the following Formula [Q-607] and the compound having ketoneor formyl.

As a compound of Formula [Q-607], a commercially available product suchas 4-bromo-2-chloro-1-iodobenzene, 5-bromo-1,3-difluoro-2-iodobenzene,4-bromo-2-ethyliodobenzene, and 5-bromo-2-iodo-m-xylene may be used.Alternatively, 2-benzyloxy-4-bromo-1-iodo-benzene which a commerciallyavailable 5-bromo-2-iodophenol is benzylated by a known method is alsoillustrated.

The compound having ketone or formyl includes the compound having ketonesuch as spiro-C₆₋₁₁ cycloalkanone and C₄₋₆ cycloalkanone or the compoundhaving formyl such as C₄₋₈ alkylaldehyde.

For example, when spiro-C₆₋₁₁ cycloalkanone as the compound havingketone or formyl is spiro[3.3]heptan-2-one, a compound of Formula[Q-607] may be reacted as follows to prepare a compound of the followingFormula [Q-612].

In the formula, each symbol has the same meaning as defined above.

Step 1

A compound of Formula [Q-609] may be prepared by a halogen-metalexchange reaction of a compound of Formula [Q-607] withisopropylmagnesium chloride and the like, followed by an additionreaction with a compound of Formula [Q-608].

A solvent includes THE and DME. A reaction temperature includes from−45° C. to room temperature.

Step 2

A compound of Formula [Q-610] may be prepared by a mesylation reactionof a compound of Formula [Q-609] in the presence of a base.

A mesylating agent includes methanesulfonyl chloride.

A base includes triethylamine and diisopropylethylamine. A preferablebase is triethylamine. A catalytic amount of trimethylaminehydrochloride and the like may be added if needed.

A solvent includes benzene, toluene, dichloromethane, chloroform,tetrahydrofuran, acetonitrile, and acetone. A preferable solvent istoluene.

A reaction temperature includes from 0° C. to 60° C. A preferablereaction temperature is from 0° C. to room temperature.

Step 3

A compound of Formula [Q-611] may be prepared by a catalytichydrogenation of a compound of Formula [Q-610] in the presence of acatalyst.

A catalyst includes palladium carbon, platinum carbon, rhodium carbon,and rhodium-alumina. A preferable catalyst is rhodium carbon.

A solvent includes methanol, ethanol, isopropanol, tetrahydrofuran,1,2-dimethoxyethane, and ethyl acetate, and may be used alone or bymixture of two or more of them. A preferable solvent is a mixed solventof methanol and tetrahydrofuran.

A compound of Formula [Q-611] may be also prepared by reducing acompound of Formula [Q-609] in the presence of Lewis acid.

Lewis acid includes boron trifluoride diethyl ether.

A reducing agent includes triethylsilane.

A solvent includes dichloromethane and tetrahydrofuran. A preferablesolvent is dichloromethane.

A reaction temperature includes from −78° C. to room temperature. Apreferable reaction temperature is from −78° C. to room temperature.

Step 4

A compound of Formula [Q-612] may be prepared from a compound of Formula[Q-611] according to an insertion reaction of carbon monoxide inPreparation Method 6-3.

The corresponding formyl, acetyl or ethylcarbonyl compound of Formula[Q-101a], [Q-301] or [Q-401a] may be prepared from a compound of Formula[Q-612] according to Preparation Method 6-1.

The following compound may be prepared with a ketone compound of “C₃₋₆cycloalkyl substituted with the same or different one to two C₁₋₅alkyl”, e.g. 3-isopropyl-cyclobutanone, as described above.

Preparation Method 6-5

A compound of Formula [Q-102], an intermediate of Preparation Method 1,e.g. a compound of Formula [Q-617] wherein R² is chloro and R⁶ is methyland the like, may be prepared by the following method.

Step 1

A compound of Formula [Q-614] may be prepared by esterifying a compoundof Formula [Q-613]. For example, when thionyl chloride and methanol areused, methyl ester may be obtained. As a compound of Formula [Q-613], acommercially available product such as 2-(4-hydroxy-phenyl)-propionicacid may be used.

Step 2

A compound of Formula [Q-615] may be prepared by chlorination of acompound of Formula [Q-614] with N-chlorosuccinimide (NCS) and the like.

A solvent includes acetonitrile and N,N-dimethylformamide. A preferablesolvent is N,N-dimethylformamide.

Step 3

A compound of Formula [Q-616] may be prepared by reacting a compound ofFormula [Q-615] with trifluoromethanesulfonic anhydride in the presenceof a base.

A base includes triethylamine and pyridine. A preferable base ispyridine.

A solvent includes toluene, dichloromethane, chloroform, andtetrahydrofuran. A preferable solvent is dichloromethane.

A reaction temperature includes from 0° C. to room temperature. Apreferable reaction temperature is 0° C.

Step 4

A compound of Formula [Q-617] may be prepared from a compound of Formula[Q-616] by a cross-coupling reaction (e.g. Suzuki reaction andSonogashira reaction) as described in Preparation Method 2-2.

When Sonogashira reaction is carried out, the resulted alkynylenecompound may be converted into an alkylene compound by a catalytichydrogenation with a catalyst such as palladium carbon, platinum carbon,and rhodium-alumina.

Steps after Step 4

A compound of Formula [I] wherein R² is chloro and R⁶ is methyl and thelike (i.e., a compound of Formula [I-Ca]) may be prepared with acompound of Formula [Q-617] by the reactions described in PreparationMethod 1.

Preparation Method 7 A Method for Preparing Starting Materials (1)Preparation Method 7-1

As a compound of Formula [Q-104]:

wherein each symbol has the same meaning as defined above, acommercially available compound such as 4-methyl-2-pentan-1-ol,4-methyl-2-hexen-1-ol, 4,4-dimethyl-2-penten-1-ol, and2,4-dimethyl-2-penten-1-ol may be used, which may be alternativelyprepared by the following method.

In the formula, each symbol has the same meaning as defined above.

Step 1

A compound of Formula [Q-702] may be prepared from a compound of Formula[Q-701] and alkylphosphonic diester such as triethyl phosphonoacetateunder Horner-Wadsworth-Emmons Reaction.

Step 2

A compound of Formula [Q-104] may be prepared from a compound of Formula[Q-702] by DIBAL reduction according to Preparation Method 6-1 Step 2.

As a compound of Formula [Q-701], a commercially available aldehyde suchas 2-methylpropylaldehyde, isovaleraldehyde, 3,3-dimethylbutylaldehyde,and 4-methylpentylaldehyde may be used, which may be alternativelyprepared by a known method.

A method for preparing a compound of Formula [Q-701] (1) For example, acompound of Formula [Q-701 a] may be prepared from a compound of Formula[Q-703].

In the formula, each symbol has the same meaning as defined above.

Step 1

A compound of Formula [Q-704] may be prepared by protecting a hydroxylgroup of a compound of Formula [Q-703] (e.g. a commerically availablecompound such as 2,2-dimethyl-3-hydroxypropanoic acid methyl ester,4-hydroxy-2,2-dimethyl-butanoic acid methyl ester, and5-hydroxy-2,2-dimethyl-pentanoic acid methyl ester) with trimethylsilyl(TMS), tert-butyldimethylsilyl (TBS) and the like according to a methoddescribed in a literature (e.g. a method described in Peter G. M. Wuts(2007). Green's Protective Groups in Organic Synthesis Fourth Edition,Weinheim, Germany, Wiley-VCH, 165-215).

Step 2

A compound of Formula [Q-705] may be prepared from a compound of Formula[Q-704] under DIBAL reduction according to Preparation Method 6-1 Step2.

Step 3

A compound of Formula [Q-701a] may be for example prepared byParikh-Doering oxidation reaction of a compound of Formula [Q-705] withSO₃·Py.

A method for preparing a compound of Formula [Q-701] (2)

A compound of Formula [Q-701b] may be also prepared from C₃₋₆cycloalkanone optionally substituted with the same or different one tothree substituent(s) selected from Group X^(b) and Wittig reagentaccording to a method described in a literature (e.g. a method describedin Bioorg. Med. Chem. Lett. 2004, 14(20), 5199-5203). For example, whenR^(3q1) is cyclohexyl, the following is illustrated.

Preparation Method 7-2

As a compound of Formula [Q-302]:

wherein each symbol has the same meaning as defined above,a commercially available aldehyde or ketone such as3,3-dimethyl-butylaldehyde, 4-methyl-pentanal, cyclohexyl-acetaldehyde,and 2-butanone may be used, which may be alternatively prepared by aknown method. For example, a compound of Formula [Q-302] wherein R⁴ is H(i.e., an aldehyde compound) may be prepared from a compound of Formula[Q-701] under a carburation reaction according to a method described ina literature (e.g. a method described in Bioorg. Med. Chem. Lett. 2004,14 (20), 5199-5203). For example, a compound of Formula [Q-302] whereinR⁴ is methyl (i.e., a ketone compound) may be prepared from a compoundof Formula [Q-701] under a carburation reaction according to a methoddescribed in a literature (e.g. a method described in Tetrahedron Lett.2009, 50, 1276-1278).

Preparation Method 7-3

As a compound of Formula [Q-404]:

wherein each symbol has the same meaning as defined above,a commercially available ester such as 3-methyl-butanoic acid methylester, 4-methylvaleric acid methyl ester (i.e., 4-Methyl-pentanoic acidmethyl ester), and 5-methylhexanoic acid methyl ester may be used, whichmay be alternatively prepared by a known method.

A methyl ester of a compound of Formula [Q-404] may be replaced with anethyl ester.

The ester compound may be, for example, prepared from a compound where ahydroxyl group of C₃₋₆ cycloalkanone optionally substituted with thesame or different one to three substituent(s) selected from Group X^(b)or a commerically available product such as 1-hydroxypropan-2-one,1-hydroxybutan-2-one, and 1-hydroxypentan-2-one is protected with TBDPS,benzyl and the like under Horner-Wadsworth-Emmons Reaction and the likeusing alkylphosphonic diester.

For example, a compound of Formula [Q-404a] may be synthesized by thefollowing preparation method.

In the formula, each symbol has the same meaning as defined above.

Step 1

A compound of Formula [Q-707] may be prepared from a compound of Formula[Q-706] by a protecting reaction of alcohol according to PreparationMethod 7-1.

Step 2

A compound of Formula [Q-708] may be prepared from a compound of Formula[Q-707] under Homer-Wadsworth-Emmons Reaction according to PreparationMethod 7-1 Step 1.

Step 3

A compound of Formula [Q-404a] may be prepared from a compound ofFormula [Q-708] by 1,4-addition reaction with methyllithium in thepresence of a copper catalyst (e.g. a method described in J. Am. Chem.Soc. 2009, 131(44), 16016-16017).

Preparation Method 8 A Method for Preparing Starting Materials (2)Preparation Method 8-1

As a compound of Formula [Q-408]:

wherein each symbol has the same meaning as defined above,a commercially available product such as 6-isocyanate-hexanoic acidethyl ester, 2-methyl-propionic acid methyl ester,3-isocyanate-propionic acid methyl ester,4-isocyanate-cyclohexanecarboxylic acid methyl ester, and4-isocyanatebenzoic acid ethyl ester may be used, which may bealternatively prepared by a known method.

For example, a compound of Formula [Q-408] may be prepared by thefollowing method.

In the formula, each symbol has the same meaning as defined above.

A compound of Formula [Q-408] may be prepared from a compound of Formula[Q-801](e.g. a commercially available product such as3-(methoxycarbonyl)bicyclo[1.1.1]pentane-1-carboxylic acid,1-(2-methoxy-2-oxoethyl)-5-oxopyrrolidine-3-carboxylic acid, and3-[1-(ethoxycarbonyl)cyclopropyl]propanoic acid) by an azidationreaction, followed by Curtius rearrangement reaction according toPreparation Method 1 Step 5.

Preparation Method 8-2

As a compound of Formula [Q-108]:

wherein each symbol has the same meaning as defined above,a commercially available product such as methyl 3-aminopropanoate,methyl 3-aminocyclopentanecarboxylate, tert-butyl2-(2-aminoethoxy)acetate, ethyl 4-aminobenzoate, and methyl3-aminobicyclo[1.1.1]pentane-1-carboxylate hydrochloride may be used,which may be alternatively prepared by a known method.

For example, a compound of Formula [Q-108] may be prepared by reacting acompound of Formula [Q-408] with benzyl alcohol or t-BuOH to protect anamino group with tert-butoxycarbonyl group (Boc group) orbenzyloxycarbonyl group (Cbz group), followed by deprotection of the Bocgroup or Cbz group according to a known method (e.g. a method describedin Peter G. M. Wuts (2007). Green's Protective Groups in OrganicSynthesis Fourth Edition, Weinheim, Germany, Wiley-VCH, 725-735,748-756).

In the formula, each symbol has the same meaning as defined above.

Preparation Method 8-3

As a compound of Formula [Q-303]:

wherein each symbol has the same meaning as defined above,a commercially available urea compound such as ureido-acetic acid ethylester, 2,2-dimethyl-3-ureido-propionic acid ethyl ester,3-ureido-cyclohexanecarboxylic acid ethyl ester, and 4-ureido-benzoicacid ethyl ester may be used, which may be alternatively prepared by aknown method.

For example, a compound of Formula [0-303] may be prepared by thefollowing method.

In the formula, each symbol has the same meaning as defined above.

A compound of Formula [Q-303] may be prepared from a compound of Formula[Q-108] and trimethylsilyl isocyanate.

A base includes triethylamine, diisopropylethylamine, anddimethylaminopyridine (DMAP), and may be used alone or by mixture of twoor more of them. A preferable base is a mixture of triethylamine anddimethylaminopyridine.

A solvent includes benzene, toluene, tetrahydrofuran, dichloromethane,chloroform, ethyl acetate, and acetonitrile. A preferable solvent istetrahydrofuran.

A reaction temperature includes from under ice cooling to 120° C. Apreferable reaction temperature is 80° C.

Preparation Method 9

A racemate of Formula [I] obtained in Preparation Method 1, 2 or 3 or aracemate of Formula [Q-110] or Formula [Q-201], an intermediate of acompound of Formula [I], may be separated into a desirable enantiomer byliquid chromatography using a chiral stationary phase.

For example, a racemate [Q-901] which “R⁶ is methyl” and “R⁵ is—Y^(c)—COO—C₂H₅” in the following formula may be separated and isolatedinto a compound of Formula [Q-902] and a compound of Formula [Q-E-902]by liquid chromatography using a chiral stationary phase, followed byhydrolysis of each isolated enantiomer to give a desirable compound.

A separation condition is for example any of the followings. A mobilephase may be optionally adjusted depending on polarities of compoundsand a mixing ratio of each solvent may be modified.

Separation condition A:

Separation instrument; Recycling preparative chromatograph LC-9225 NEXTSERIES Japan Analytical Industry Co., Ltd.

-   -   Column; DAICEL CHIRALPAK IA 2.0 cmφ×25 cm    -   Mobile phase; hexane:2-propanol=90:10    -   Flow rate; 10.0 mL/min    -   Detection; UV (254 nm)

Separation condition B:

Separation instrument; Recycling preparative chromatograph. LC-9225 NEXTSERIES Japan Analytical Industry Co., Ltd.

-   -   Column; Japan Analytical industry Co., Ltd. JAIGEL-ODS-AP,        SP-120-10, 2.0 cmφ×25 cm    -   Mobile phase; acetonitrile:H₂O:formic acid=90:10:0.1    -   Flow rate; 10.0 mL/min    -   Detection; UV (220 nm)

The following abbreviations may be for example used herein:

-   -   DMF: dimethylformamide    -   TBAF: tetrabutylammonium fluoride    -   NMP: N-methylpyrrolidone    -   Grubbs Cat. 2nd:        (1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro-(phenylmethylene)(tricyclohexylphosphine)ruthenium        PdCl₂(dppf):        dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium

EXAMPLES

In particular, a method for preparing a compound of Formula [I] or apharmaceutically acceptable salt thereof is illustrated by Examples. Amethod for preparation of a compound of Formula [I] or apharmaceutically acceptable salt thereof is however not limited to themethod for preparation.

For example, to “purify through silica gel column chromatography (ethylacetate:hexane=1:50->1:5)” means a procedure for elution with a mixedsolution with a mixed ratio of 1:50 (ethyl acetate:hexane), followed byelution with a mixed solution with a mixed ratio of 1:5 (ethylacetate:hexane) in a purification through silica gel columnchromatography. “d.r.” means a diastereomer ratio. A melting point isdetermined by a melting point determination apparatus (Yanaco MP-500D,manufactured by Yanagimoto Seisakujo).

Example 5 Preparation of4-{5-tert-butyl-4-[3-chloro-4-(2,2-dimethylpropoxy)-phenyl]-2-oxo-3,4-dihydro-2H-pyrimidin-1-yl}-butanoicacid (Optically Active Compound) Step 13-chloro-4-(2,2-dimethylpropoxy)-benzaldehyde

3-Chloro-4-hydroxybenzaldehyde (5 g) and 1-iodo-2,2-dimethylpropane (8-5mL) were mixed in N,N-dimethylformamide (25 mL). To the reactionsolution was added cesium carbonate (4.43 g), and the reaction solutionwas stirred at 100° C. overnight. To the reaction solution was addedwater, and then the mixture was extracted with ethyl acetate. Theorganic layer was sequentially washed with water and aqueous saturatedsodium chloride solution, and dried over magnesium sulfate. Afterremoving magnesium sulfate on a filter, the filtrate was concentratedunder reduced pressure to give the titled compound (4.82 g).

Step 2 4-Carbamoylaminobutanoic acid ethyl ester

4-Aminobutyric acid ethyl hydrochloride (3.00 g), triethylamine (2.49mL), and 4-dimethylaminopyridine (218 mg) were mixed in tetrahydrofuran(40 mL). To the reaction solution was added trimethylsilyl isocyanate(2.37 mL), and the reaction solution was stirred at 80° C. for 3.5hours. To the reaction solution was added ethyl acetate under icecooling. After removing an insoluble on a filter, the filtrate wasconcentrated under reduced pressure. The solid precipitated by addingdiisopropylether to the resulted residue was filtered to give the titledcompound (2.48 g).

Step 34-{5-tert-Butyl-4-[3-chloro-4-(2,2-dimethylpropoxy)-phenyl]-2-oxo-3,4-dihydro-2H-pyrimidin-1-yl}-butanoicacid ethyl ester (Optically Active Compound)

3-Chloro-4-(2,2-dimethylpropoxy)-benzaldehyde (510 mg) and4-carbamoylaminobutanoic acid ethyl ester (261 mg) were mixed inacetonitrile (1.6 mL) and N,N-dimethylformamide (0.8 mL). To thereaction solution was added trimethylchlorosilane (0.19 mL), and thereaction solution was stirred for 30 minutes. To the reaction solutionwas added 3,3-dimethylbutylaldehyde (0.19 mL), and the reaction solutionwas stirred at 80° C. for 2.5 hours. Water was added to the reactionsolution at room temperature, which was then extracted with ethylacetate. The organic layer was sequentially washed with water andaqueous saturated sodium chloride solution, and dried over magnesiumsulfate. After removing magnesium sulfate on a filter, the filtrate wasconcentrated under reduced pressure. The resulted residue was purifiedthrough silica gel chromatography (ethyl acetate:chloroform=1:2),followed by thin layer silica gel chromatography (ethylacetate:chloroform=1:2), to give a racemate of the titled compound(147.4 mg). The racemate was separated and purified by recyclingpreparative chromatograph.

The titled compound (64.5 mg) was obtained as a compound in a fractioneluted earlier in recycling preparative chromatograph (separationcondition A1). The compound was analyzed by analytical column DAICELCHIRALPAK IA-3 (analytical condition B1) to determine 6.6 min as theretention time and >99% ee as the optical purity.

An enantiomer of the titled compound (i.e., an ethyl ester of Example 6)was obtained as a compound in a fraction eluted later in recyclingpreparative chromatograph (separation condition A1). The compound wasanalyzed by analytical column DAICEL CHIRALPAK IA-3 (analyticalcondition B1) to determine 9.5 min as the retention time and >99% ee asthe optical purity.

The separation condition was as follows.

(Separation Condition A1)

-   -   Separation instrument; Recycling preparative chromatograph        LC-9225 NEXT SERIES Japan Analytical Industry Co., Ltd.    -   Column; DAICEL CHIRALPAK IA 2.0 cmφ×25 cm    -   Mobile phase; hexane:2-propanol=70:30    -   Flow rate; 10.0 mL/min    -   Detection; UV (220 nm)

The analytical condition used in the chiral column was as follows.

(Analytical Condition B1)

-   -   Measuring instrument; HPLC system Shimadzu Corporation        high-performance liquid chromatograph prominence    -   Column; DAICEL CHIRALPAK IA-3 0.46 cmφ×15 cm    -   Column temperature; 40° C.    -   Mobile phase; hexane:2-propanol=80:20    -   Flow rate; 1.0 mL/min    -   Detection; UV (220 nm)

Step 44X-{5-tert-Butyl-4-[3-chloro-4-(2,2-dimethylpropoxy)-phenyl]-2-oxo-3,4-dihydro-2H-pyrimidin-1-yl}-butanoicacid (Optically Active Compound)

4-{5-tert-Butyl-4-[33-chloro-4-(2,2-dimethylpropoxy)-phenyl]-2-oxo-3,4-dihydro-2H-pyrimidin-1-yl}-butanoicacid ethyl ester (63 mg) obtained in Step 3 was mixed in ethanol (0.5mL). To the reaction solution was added 4M aqueous lithium hydroxidesolution (0.07 mL), and the reaction solution was stirred at roomtemperature for 3.5 hours. To the reaction solution were added 2Maqueous hydrochloric acid solution and water under ice cooling, whichwas then extracted with ethyl acetate. The organic layer was washed withaqueous saturated sodium chloride solution, and dried over magnesiumsulfate. After removing magnesium sulfate on a filter, the filtrate wasconcentrated under reduced pressure. To the resulted residue was added amixed solvent of hexane-diisopropylether (1:1), and the precipitatedsolid was filtered to give the titled compound (47.8 mg).

The resulted compounds were analyzed with a chiral column to determine13.5 min as the retention time and >99% ee as the optical purity of theresulted enantiomer compound. The retention time of the other enantiomerwas 16.7 min.

The analytical condition used in the chiral column was as follows.

-   -   Measuring instrument; HPLC system Shimadzu Corporation        high-performance liquid chromatograph prominence    -   Column; DAICEL CHIRALPAK AS-3R 0.46 cmφ×15 cm    -   Column temperature; 40° C.    -   Mobile phase; water:acetonitrile:trifluoroacetic acid=30:70:0.1    -   Flow rate; 0.5 mL/min    -   Detection; UV (220 nm)

Example 87 Preparation of3-{(S)-4-[3-chloro-4-(3,3-dimethyl-butyl)-phenyl]-5-isopropyl-4-methyl-2-oxo-3,4-dihydro-2H-pyrimidin-1-yl}-propionicacid (A Method for Preparation Using an Optically Active Sulfinamide)Step 1 4-Bromo-3-chloro-N-methoxy-N-methyl-benzamide

4-Bromo-3-chloro-benzoic acid (100 g), N,O-dimethylhydroxylaminehydrochloride (49.7 g), 1-hydroxybenzotriazole monohydrate (13.0 g), anddiisopropylethylamine (103.8 mL) were mixed in acetonitrile (800 mL). Tothe reaction solution was added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (97.6 g) infour batches under ice cooling, and the reaction solution was stirred atroom temperature overnight. To the reaction solution were added toluene(1 L) and water (500 mL), and the mixture was separated, and then theaqueous layer was extracted with toluene (500 ml) twice. The resultedorganic layer was collected and washed sequentially with 1M hydrochloricacid, water, saturated aqueous sodium hydrogen carbonate solution, andaqueous saturated sodium chloride solution, and dried over magnesiumsulfate. After removing magnesium sulfate on a filter, the filtrate wasconcentrated under reduced pressure to give the titled compound (115.8g) as a crude product.

¹H-NMR (400 MHz, CDCl3) 3.36 (s, 3H), 3.55 (s, 3H), 7.47 (dd, 0.1=8.32,1.85 Hz, 1H), 7.66 (d, J=8.32 Hz, 1H), 7.81 (d, J=1.85 Hz, 1H)

Step 2 1-(4-Bromo-3-chloro-phenyl)-ethanone

4-Bromo-3-chloro-N-methoxy-N-methyl-benzamide (115 g) was mixed intetrahydrofuran (575 mL). To the reaction solution was added dropwise 1Mmethylmagnesium bromide/tetrahydrofuran solution (516 mL) under icecooling, and the reaction solution was stirred for 2 hours under icecooling. To the reaction solution was added dropwise 1M hydrochloricacid (550 mL) under ice cooling, and then to the mixture was added ethylacetate (500 ml). The mixed solution was separated, and the aqueouslayer was then extracted with ethyl acetate. The resulted organic layerwas collected and washed sequentially with water and aqueous saturatedsodium chloride solution, and dried over magnesium sulfate. Afterremoving magnesium sulfate on a filter, the filtrate was concentratedunder reduced pressure. To the resulted residue were addeddiisopropylether and hexane, and the precipitated solid was filtered togive the titled compound (91.5 g).

¹H-NMR (400 MHz, CDCl₃) 2.59 (s, 3H), 7.68 (dd, J=8.32, 1.85 Hz, 1H),7.74 (d, J=8.32 Hz, 1H), 8.02 (d, J=1.85 Hz, 1H)

Step 3 1-[3-Chloro-4-(3,3-dimethyl-but-1-ynyl)-phenyl]-ethanone

1-(4-Bromo-3-chloro-phenyl)-ethanone (78 g), triethylamine (390 mL),3,3-dimethyl-but-1-yne (53.2 mL), and copper iodide (6.4 g) were mixedin N,N-dimethylformamide (46 mL) under argon gas. To the reactionsolution was added bis(triphenylphosphine)palladium (II) dichloride(23.5 g), and the reaction solution was stirred at 90° C. for 2 hours.To the reaction solution were added saturated ammonium chloride water, amixed solution of ethyl acetate-hexane (1:1), and Celite at roomtemperature, and the mixture was stirred for 10 minutes. After removingan insoluble on a filter, the filtrate was extracted with a mixedsolution of ethyl acetate-hexane (1:1). The organic layer wassequentially washed with aqueous saturated ammonium chloride solution,0.5M hydrochloric acid, water, and aqueous saturated sodium chloridesolution, and dried over magnesium sulfate. After removing magnesiumsulfate on a filter, the filtrated was concentrated under reducedpressure. The resulted residue was purified through silica gel columnchromatography (ethyl acetate:hexane=1:30->1:13) to give the titledcompound (75.37 g).

¹H-NMR (400 MHz, CDCl₃) 1.35 (s, 9H), 2.58 (s, 3H), 7.49 (d, J=7.97 Hz,1H), 7.74 (dd, J=7.97, 1.69 Hz, 1H), 7.95 (d, J=1.69 Hz, 1H)

Step 4 1-[3-Chloro-4-(3,3-dimethyl-butyl)-phenyl]-ethanone

1-[3-Chloro-4-(3,3-dimethyl-but-1-ynyl)-phenyl]-ethanone (22.3 g) wasmixed in tetrahydrofuran (112 mL) and methanol (112 mL). To the reactionsolution was added 5 w/w % rhodium/alumina (2.23 g), and the reactionsolution was stirred for 8.5 hours under hydrogen gas at ordinarypressure. After removing rhodium/alumina on a filter, the filtrate wasconcentrated under reduced pressure. The procedure was repeated two moretimes, and the resulted residue was collected and purified throughsilica gel chromatography (ethyl acetate:hexane=1:50) to give the titledcompound (58.0 g).

¹H-NMR (400 MHz, CDCl₃) 0.98 (s, 9H), 1.45-1.48 (m, 2H), 1.54 (s, 3H),2.57 (s, 3H), 2.72-2.76 (m, 2H), 7.31 (d, J=7.92 Hz, 1H), 7.76 (dd,J=7.92, 1.79 Hz, 1H), 7.92 (d, J=1.79 Hz, 1H)

Step 5

-   -   (S)-2-Methyl-propane-2-sulfinic acid        [1-[3-chloro-4-(3,3-dimethyl-butyl)-phenyl]-eth-(E)-ylidene]-amide

1[3-Chloro-4-(3,3-dimethyl-butyl)-phenyl]-ethanone (56.1 g) and(S)-(−)-2-methyl-propane-2-sulfinic acid amide (29.05 g) were mixed incyclopentylmethyl ether (234 mL). To the reaction solution was addedtetraethyl orthotitanate (98.3 mL), and the reaction solution wasstirred at 110° C. for 4.5 hours. The solution was added dropwise to amixed solution of 10 w/w % aqueous ammonium chloride solution (300mL)-ethyl acetate (200 mL) under ice cooling, and the mixed solution wasstirred at room temperature for 30 minutes. To the mixed solution wasadded Celite, and the mixed solution was stirred for additional 30minutes at room temperature. After removing an insoluble on a filter,the filtrate was washed sequentially with 30 w/w % aqueous ammoniumchloride solution and aqueous saturated sodium chloride solution, anddried over sodium sulfate. After removing sodium sulfate on a filter,the filtrate was concentrated under reduced pressure. The resultedresidue was purified through silica gel column chromatography (ethylacetate:hexane=1:50->1:33->1:20->1:10->1:5) to give the titled compound(69.86 g).

¹H-NMR (400 MHz, CDCl₃) 0.99 (s, 9H), 1.32 (s, 9H), 1.45-1.47 (m, 2H),2.70-2.75 (m, 2H), 2.73 (s, 3H), 7.26 (d, J=8.09 Hz, 1H), 7.68 (dd,3=−8.09, 1.74 Hz, 1H), 7.84 (d, J=1.74 Hz, 1H)

Step 6(R)-3-Chloro-4-(3,3-dimethyl-butyl)-phenyl]-2-isopropy1-3-((S)-2-methyl-propane-2-sulfinylamino)-butanoicacid methyl ester

Diisopropylamine (52.7 mL) was mixed in tetrahydrofuran (341 mL) underargon gas. To the reaction solution was added dropwise 1.63 Mn-butyllithium/hexane solution (220 mL) at −78° C., and the reactionsolution was stirred at −78° C. for 40 minutes. To the reaction solutionwas added dropwise a mixed solution of 3-methyl-butanoic acid methylester (45 mL) in tetrahydrofuran (34 mL), and the reaction solution wasstirred at −78° C. for additional 1 hour. To the reaction solution wasadded dropwise 1 M chloro titanium (IV) triisopropoxide/hexane solution(682 mL), and the reaction solution was stirred at −78° C. foradditional 30 minutes. To the reaction solution was added dropwise amixed solution of (S)-2-methyl-propane-2-sulfinic acid[1-[3-chloro-4-(3,3-dimethyl-butyl)-phenyl]-eth-(E)-ylidene]-amide(60.73 g) in tetrahydrofuran (34 mL), and the reaction solution wasstirred at −78° C. for 10 minutes, then at −40° C. for additional 2hours. The reaction solution was cooled to −78° C. and was dropped underice cooling to aqueous ammonium chloride solution. The resulted mixedsolution was stirred under ice cooling for 1 hour, and then an insolublewas removed on a filter. The filtrate was separated, and the organiclayer was washed sequentially with ammonium chloride water and aqueoussodium chloride solution and dried over sodium sulfate. After removingsodium sulfate on a filter, the filtrate was concentrated under reducedpressure. The resulted residue was purified through silica gel columnchromatography (ethyl acetate:hexane=1:20->1:10->1:4->1:3) to give thetitled compound (64.91 g) as a mixture of diastereomers generated byisopropyl group at α-position of ester (d.r.=90:10).

¹H-NMR (400 MHz, CDCl₃) 0.72 (d, J=6.82 Hz, 0.3H), 0.92 (d, J=2.31 Hz,2.7H), 0.93 (d, J=2.31 Hz, 2.7H), 0.98 (s, 8.1H), 0.99 (s, 0.9H), 1.01(d, J=6.82 Hz, 0.3H), 1.25 (s, 8.1H), 1.34 (s, 0.9H), 1.44-1.49 (m, 2H),1.86 (s, 0.3H), 1.89 (s, 2.7H), 2.01-2.11 (m, 1H), 2.46 (d, J=3.93 Hz,0.1H), 2.63-2.72 (m, 2H), 2.83 (d, J=3.93 Hz, 0.9H), 3.59 (s, 2.7H),3.70 (s, 0.3H), 5.04 (brs, 0.9H), 5.42 (brs, 0.1H), 7.13-7.27 (m, 2H),7.39 (d, J=2.08 Hz, 0.9H), 7.43 (d, J=1.85 Hz, 0.1H)

Step 7 (S)-2-Methyl-propane-2-sulfinic acid{(R)-1-[3-chloro-4-(3,3-dimethyl-butyl)-phenyl]-2-hydroxymethyl-1,3-dimethyl-butyl}amide

(R)-3-[3-Chloro-4-(3,3-dimethyl-butyl)-phenyl]-2-isopropyl-3-((S)-2-methyl-propane-2-sulfinylamino)-butanoicacid methyl ester (54.9 g) was mixed in toluene (384 mL) under argongas. To the reaction was added dropwise 1 M diisobutylaluminumhydride/toluene solution (415 mL) at −78° C., and the reaction solutionwas stirred at −78° C. for 50 minutes, then gradually warmed to 0° C. tostir for 3 hours. To the reaction solution was added dropwise under icecooling methanol, then aqueous Rochelle salt solution. To the mixedsolution was added ethyl acetate, and then the mixture was stirred atroom temperature for 3 hours. The resulted solution was extracted withethyl acetate. The organic layer was washed sequentially with water andaqueous saturated sodium chloride solution, and dried over sodiumsulfate. After removing sodium sulfate on a filter, the filtrate wasconcentrated under reduced pressure. To the resulted residue was addeddiisopropylether, and the precipitated solid was filtered to give thetitled compound (42.0 g, d.r.=95:5).

¹H-NMR (400 MHz, CDCl₃) 0.70 (d, J=7.06 Hz, 3H), 0.75 (d, J=7.06 Hz,3H), 0.99 (s, 9H), 1.15 (s, 9H), 1.17-1.26 (m, 1H), 1.47-1.52 (m, 2H),1.94 (s, 3H), 2.04-2.09 (m, 1H), 2.65-2.71 (m, 2H), 3.91-3.96 (m, 1H),3.99-4.06 (m, 1H), 4.75 (s, 1H), 6.63 (s, 1H), 7.17 (d, J=8.04 Hz, 1H),7.23 (dd, J=8.04, 1.91 Hz, 1H), 7.40 (d, J=1.91 Hz, 1H) (for the majorisomer)

An absolute configuration of the quaternary asymmetric carbon in thetitled compound was determined by purification of the major isomer ofthe titled compound (i.e. the following compound), followed by singlecrystal X-ray structural analysis thereof.

Step 8(R)-3-Amino-3-[3-chloro-4-(3,3-dimethyl-butyl)-phenyl]-2-isopropyl-butan-1-ol

(S)-2-Methyl-propane-2-sulfinic acid{(R)-1-[3-chloro-4-(3,3-dimethyl-butyl)-phenyl]-2-hydroxymethyl-1,3-dimethyl-butyl}amide(41.4 g) was mixed in methanol (207 mL) and tetrahydrofuran (21 ml). Tothe reaction solution was added dropwise 2M hydrogen chloride/methanolsolution (193 mL) under ice cooling, and the reaction solution wasstirred at room temperature for three hours. The reaction solution wasconcentrated under reduced pressure, and chloroform was added to theresidue. An aqueous sodium carbonate solution was added to the mixedsolution under ice cooling so that the aqueous layer was adjusted to pH10. The mixed solution was extracted with chloroform. The organic layerwas washed with aqueous saturated sodium chloride solution, and driedover sodium sulfate. After removing sodium sulfate on a filter, thefiltrate was concentrated under reduced pressure to give the titledcompound (29.0 g, d.r.=95:5) as a crude product.

¹H-NMR (400 MHz, CDCl₃) 0.80 (d, J=7.00 Hz, 3H), 0.85 (d, J=7.00 Hz,3H), 0.98 (s, 9H), 1.35-1.42 (m, 1H), 1.43-1.49 (m, 2H), 1.60 (s, 3H),1.86-1.91 (m, 1H), 2.65-2.70 (m, 2H), 3.70 (dd, J=11.59, 3.38 Hz, 5H),3.92 (dd, J=11.59, 9.18 Hz, 1H), 7.21-7.22 (m, 2H), 7.36 (d, J=1.69 Hz,1H) (for the major isomer)

Step 93-(3-{(R)-1-[3-Chloro-4-(3,3-dimethyl-butyl)-phenyl]-2-hydroxymethyl-1,3-dimethyl-butyl}-ureido)-propionicacid ethyl ester

(R)-3-Amino-3-[3-chloro-4-(3,3-dimethyl-butyl)-phenyl]-2-isopropyl-butan-1-ol(29.0 g) was mixed in tetrahydrofuran (203 mL). To the reaction solutionwas added 3-isocyanatopropionic acid ethyl ester (11.8 mL) under icecooling, and the reaction solution was stirred at room temperature for100 minutes. To the reaction solution was added 3-isocyanatopropionicacid ethyl ester (1.18 mL) under ice cooling, and the reaction solutionwas stirred at room temperature for 75 minutes. To the reaction solutionwas added 3-isocyanatopropionic acid ethyl ester (0.59 mL) at roomtemperature, and the reaction solution was stirred at room temperaturefor 2 hours. To the mixed solution was addedN,N,N-trimethylethylenediamine (1.73 mL), and the mixture was stirred atroom temperature for 40 minutes. To the reaction solution was added 0.1Mhydrochloric acid, which was extracted with ethyl acetate. The organiclayer was washed sequentially with water, aqueous saturated sodiumchloride solution, and aqueous sodium chloride solution, and dried oversodium sulfate. After removing sodium sulfate on a filter, the reactionsolution was concentrated under reduced pressure, and the resultedresidue was purified through silica gel column chromatography (ethylacetate:chloroform=1:10->1:5->1:3) to give the titled compound (41.6 g,d.r.=95:5).

¹H-NMR (400 MHz, CDCl₃) 0.77 (d, J=6.94 Hz, 3H), 0.83 (d, J=6.94 Hz,3H), 0.98 (s, 9H), 1.25 (t, J=7.03 Hz, 3H), 1.48 (dt, J=9.02, 4.05 Hz,2H), 1.52-1.58 (m, 1H), 1.71-1.74 (m, 1H), 1.79 (s, 3H), 2.33-2.45 (m,2H), 2.63-2.68 (m, 2H), 2.82 (brs, 1H), 3.31 (q, J=6.17 Hz, 2H), 3.80(d, J=11.10 Hz, 1H), 3.90-3.95 (m, 1H), 4.12 (q, J=7.03 Hz, 2H), 4.49(t, J=6.01 Hz, 1H), 7.13 (brs, 1H), 7.16 (d, J=8.15 Hz, 1H), 7.25 (dd,J−8.15, 2.03 Hz, 1H), 7.38 (d, J=2.03 Hz, 1H) (for the major isomer)

Step 103-{(S)-4-[3-Chloro-4-(3,3-dimethyl-butyl)-phenyl]-5-isopropyl-4-methyl-2-oxo-3,4-dihydro-2H-pyrimidin-1-yl}propionic acid ethyl ester

3-(3-{(R)-1-[3-Chloro-4-(3,3-dimethyl-butyl)-phenyl]-2-hydroxymethyl-1,3-dimethyl-butyl}-ureido)-propionicacid ethyl ester (17.1 g) and iodobenzene diacetate (13.3 g) were mixedin dichloromethane (143 mL). To the reaction solution was added a mixedsolution of 2.2,6,6-tetramethylpiperidine 1-oxyl free radical (17.5 mg)in dichloromethane (2 ml) under ice cooling, and the reaction solutionwas stirred at room temperature for 18 hours. To the reaction solutionwas added trifluoroacetic acid (10.78 mL) under ice cooling, and thenthe reaction solution was stirred at room temperature for 1 hour. To thereaction solution was added aqueous sodium sulfite solution under icecooling, and then thereto was added aqueous potassium hydrogen carbonatesolution. The resulted mixed solution was extracted with ethyl acetate.The organic layer was washed sequentially with water and aqueoussaturated sodium chloride solution, and dried over sodium sulfate. Afterremoving sodium sulfate on a filter, the filtrate was concentrated underreduced pressure. The resulted residue was purified through silica gelcolumn chromatography (ethyl acetate:hexane=1:20->1:9->1:7->1:4->1:3) togive the titled compound (18.3 g).

¹H-NMR (400 MHz, CDCl₃) 0.71 (d, J=6.94 Hz, 3H), 0.98 (s, 9H), 1.04 (d,J=6.94 Hz, 3H), 1.28 (t, J=7.17 Hz, 4H), 1.41-1.48 (m, 2H), 1.68 (s,3H), 1.83-1.90 (m, 1H), 2.64-2.69 (m, 4H), 3.78 (t, J=6.59 Hz, 2H), 4.16(q, J=7.17 Hz, 3H), 4.61 (s, 1H), 5.90 (s, 1H), 7.16 (d, J=8.04 Hz, 1H),7.24 (dd, J=7.94, 2.02 Hz, 1H), 7.38 (d, J=2.02 Hz, 1H)

Step 113-{(S)-4[3-Chloro-4-(3,3-dimethyl-butyl)-phenyl]-5-isopropyl-4-methyl-2-oxo-3,4-dihydro-2H-pyrimidin-1-yl}-propionicacid

3-{(S)-4-[3-Chloro-4-(3,3-dimethyl-butyl)-phenyl]-5-isopropyl-4-methyl-2-oxo-3,4-dihydro-2H-pyrimidin-1-yl}-propionicacid ethyl ester (34.8 g) obtained by repeating Example 87 (a method forpreparation using an optically active sulfinamide) Steps 1 to 10 wasmixed in ethanol (350 mL). To the reaction solution was added dropwise4M aqueous sodium hydroxide solution (38.7 mL) under ice cooling, andthe reaction solution was stirred at room temperature for 2 hours. Thereaction solution was concentrated under reduced pressure, and thenwater was added to the residue. To the mixed solution was added 6Mhydrochloric acid (25.8 mL) under ice cooling. The precipitated solidwas dissolved in ethyl acetate, and then extracted with ethyl acetate.The organic layer was washed with aqueous saturated sodium chloridesolution, and then dried over magnesium sulfate. After removing sodiumsulfate on a filter, the reaction solution was concentrated underreduced pressure. To the resulted residue was added ethanol (500 mL),which was again concentrated under reduced pressure. The resultedresidue was mixed in water (600 mL). To the reaction solution was added4M aqueous sodium hydroxide solution (26.85 mL) under ice cooling. Tothe reaction solution was added 6M hydrochloric acid (17.9 mL) under icecooling, and the reaction solution was stirred under ice cooling for 30minutes. Then 6M hydrochloric acid was added to the solution so that thereaction solution was adjusted to pH 2, and the reaction solution wasstirred under ice cooling for 30 minutes. The precipitated solid wasfiltered and dried to give the titled compound (28.9 g).

A specific optical rotation of the resulted compound was [α]_(D)²⁵+112.6 (c=1.00, methanol).

The resulted compound was analyzed with a chiral column, and theretention time of the resulted titled compound (S-enantiomer) was 9.0minutes, the optical purity of which was >99% ee.

The analytical condition using a chiral column was as follows.

-   -   Measuring instrument; HPLC system Shimadzu Corporation        high-performance liquid chromatograph prominence    -   Column; DAICEL CHIRALPAK AD-3R 0.46 cmφ×15 cm    -   Column temperature; 40° C.    -   Mobile phase; water:acetonitrile:formic acid=30:70:0.1    -   Flow rate; 0.5 mL/min    -   Detection; UV (220 nm)

The resulted solid (20 mg) was mixed in a mixed solvent of2-propanol-water (1:20, 0.21 mL), and the suspension was stirred at 60°C. for 1.5 hours. The suspension was cooled to room temperature over 1hour, and then the precipitated solid was filtered to give a crystal ofthe titled compound (18 mg). The melting point of the crystal was117.5-118.7° C.

Example 87 Preparation of3-{(S)-4-[3-chloro-4-(3,3-dimethyl-butyl)-phenyl]-5-isopropyl-4-methyl-2-oxo-3,4-dihydro-2H-pyrimidin-1-yl}-propionicacid (A Method for Preparation Using Cleisen Reaction) Step 12-(4-Hydroxy-phenyl)-propionic acid methyl ester

2-(4-Hydroxyphenyl)propionic acid (75 g) was mixed in methanol (750 mL).To the reaction solution was added dropwise thionyl chloride (49 mL),and the reaction solution was stirred at 60° C. for 3 hours. Thereaction solution was concentrated under reduced pressure, and water wasadded to the residue, which was then extracted with ethyl acetate. Theorganic layer was washed sequentially with water and aqueous saturatedsodium chloride solution, and dried over magnesium sulfate. Afterremoving magnesium sulfate on a filter, the filtrate was concentratedunder reduced pressure to give the titled compound (97 g) as a crudeproduct.

¹H-NMR (400 MHz, CDCl₃) 1.45 (d, J=7.40 Hz, 3H), 3.64-3.66 (m, 4H), 5.08(s, 1H), 6.75-6.78 (m, 2H), 7.14-7.15 (m, 2H)

Step 2 2-(3-Chloro-4-hydroxy-phenyl)-propionic acid methyl ester

2-(4-Hydroxy-phenyl)-propionic acid methyl ester (97.0 g) was mixed inN,N-dimethylformamide (450 mL). To the reaction solution was addedN-chlorosuccinimide (60.1 g), and the reaction solution was stirred at80° C. for 4 hours. To the reaction solution was added water, which wasthen extracted with toluene. The organic layer was washed with water andaqueous saturated sodium chloride solution, and dried over magnesiumsulfate. After removing magnesium sulfate on a filter, the filtrated wasconcentrated under reduced pressure to give the titled compound (101.5g) as a crude product.

¹H-NMR (400 MHz, CDCl₃) 1.45 (d, J=7.17 Hz, 3H), 3.61-3.66 (m, 4H), 5.58(s, 1H), 6.95 (d, J=8.55 Hz, 1H), 7.09 (dd, J=8.44, 1.97 Hz, 1H), 7.25(d, J=8.55 Hz, 1H)

Step 3 2-(3-Chloro-4-trifluoromethanesulfonyloxyphenyl)propionic acidmethyl ester

2-(3-Chloro-4-hydroxy-phenyl)-propionic acid methyl ester (101.5 g) wasmixed in methylene chloride (600 mL) and pyridine (73 mL) under argongas. To the reaction solution was added dropwisetrifluoromethanesulfonic anhydride (91 mL) under ice cooling, and thereaction solution was stirred at room temperature for 6.5 hours. Then tothe reaction solution was added trifluoromethanesulfonic anhydride (11.4mL), and the reaction solution was stirred at room temperatureovernight. To the reaction solution was added water, which was thenextracted with chloroform. The organic layer was washed sequentiallywith 1M hydrochloric acid, saturated aqueous sodium hydrogen carbonatesolution, and aqueous saturated sodium chloride solution, and dried overmagnesium sulfate. After removing magnesium sulfate on a filter, thefiltrate was concentrated under reduced pressure to give the titledcompound (156.69 g) as a crude product.

¹H-NMR (400 MHz, CDCl₃) 1.50 (d, J=7.17 Hz, 3H), 3.67-3.71 (m, 4H),7.27-7.28 (m, 1H), 7.46 (d, J=1.85 Hz, 1H)

Step 4 2-[3-Chloro-4-(3,3-dimethyl-but-1-ynyl)-phenyl]-propionic acidmethyl ester

2-(3-Chloro-4-trifluoromethanesulfonyloxyphenyl)propionic acid methylester (60 g), tetrabutylammonium iodide (128 g), 3,3-dimethyl-but-1-yne(42.4 mL), triethylamine (60 mL), bis(triphenylphosphine)palladium (II)dichloride (12.2 g), and copper iodide (9.88 g) were mixed inN,N-dimethylformamide (300 mL) under argon gas. The reaction solutionwas stirred at 70° C. for 1 hour. To the reaction solution was addedwater, which was then extracted with toluene. The organic layer waswashed sequentially with 1M hydrochloric acid, water, saturated aqueoussodium hydrogen carbonate solution, and saturated sodium chloride water,and dried over magnesium sulfate. After removing magnesium sulfate on afilter, the filtrate was concentrated under reduced pressure. Theresulted residue was purified through silica gel column chromatography(ethyl acetate:hexane=1:30->1:20) to give the titled compound (37.15 g).

¹H-NMR (400 MHz, CDCl₃) 1.31 (s, 911), 1.45 (d, J=7.17 Hz, 3H),3.62-3.67 (m, 4H), 7.08 (dd, J=7.86, 1.85 Hz, 1H), 7.29 (d, J=1.62 Hz,1H), 7.34 (d, J=8.09 Hz, 1H)

Step 5 2-[3-Chloro-4-(3,3-dimethyl-butyl)-phenyl]-propionic acid methylester

2-[3-Chloro-4-(3,3-dimethyl-but-1-ynyl)-phenyl]-propionic acid methylester (18.5 g) was mixed in methanol (185 mL). To the mixed solution wasadded 5 w/w % platinum/activated carbon (1.85 g), and the reactionsolution was stirred for 9 hours under hydrogen gas at 4 atm. Removalfrom the reaction solution platinum/activated carbon on a filter gave afiltrate (referred to as Filtrate A hereinafter).

According to the reduction procedure,2-[3-chloro-4-(3,3-dimethyl-but-1-ynyl)-phenyl]-propionic acid methylester (18.5 g) was treated to give a filtrate (referred to as Filtrate Bhereinafter).

Filtrate A and Filtrate B were combined and concentrated under reducedpressure to give a residue (34.08 g/referred to as Residue Chereinafter).

Residue C was analyzed (¹H-NMR measurement), which showed that thereduction reaction was not completed (i.e. a starting material wasexisted), and the reduction reaction was repeated.

Residue C (34 g) was divided into two halves of Residue D (17 g) andResidue E (17 g). Residue D (17 g) was mixed in methanol (185 mL). Tothe mixed solution was added 5 w/w %) platinum/activated carbon (1.85g), and the reaction solution was stirred for 5 hours under hydrogen gasat 4 atm. Then platinum/activated carbon was removed from the reactionsolution on a filter to give a filtrate (referred to as Filtrate Fhereinafter).

Residue E (17 g) was treated according to the reduction procedure togive a filtrate (referred to as Filtrate G hereinafter).

The resulted Filtrate F and Filtrate G were combined and concentratedunder reduced pressure to give the titled compound (35.06 g) as a crudeproduct.

¹H-NMR (400 MHz, CDCl₃) 0.97 (s, 9H), 1.42-1.48 (m, 5H), 2.63-2.68 (m,2H), 3.65-3.66 (m, 4H), 7.10 (dd, J=7.85, 1.81 Hz, 1H), 7.16 (d, J=7.97Hz, 1H), 7.26-7.27 (m, 1H)

Step 6 2-[3-Chloro-4-(3,3-dimethyl-butyl)-phenyl]-propionic acid

2[3-Chloro-4-(3,3-dimethyl-butyl)-phenyl]-propionic acid methyl ester(35.0 g) was mixed in tetrahydrofuran (110 mL) and methanol (110 ml). Tothe reaction solution was added dropwise 4M aqueous sodium hydroxidesolution (93 mL) under ice cooling, and the reaction solution wasstirred at room temperature for 2 hours. Then to the reaction solutionwas added dropwise 2M hydrochloric acid (186 mL) under ice cooling, andthe resulted mixed solution was extracted with ethyl acetate. Theorganic layer was washed sequentially with water and saturated sodiumchloride water, and then dried over sodium sulfate. After removingsodium sulfate on a filter, the filtrate was concentrated under reducedpressure. To the resulted residue was added a mixed solution ofhexane-diisopropylether (10:1), and then the precipitated solid wasfiltered. The resulted filtrate was concentrated under reduced pressure,and to the residue was added again a mixed solution ofhexane-diisopropylether (10:1), and the precipitated solid was filtered.The resulted solid was collected to give the titled compound (30.4 g).

¹H-NMR (400 MHz, CDCl₃) 0.96 (s, 9H), 1.42-1.44 (m, 2H), 1.48 (d, J=7.17Hz, 3H), 2.63-2.65 (m, 2H), 3.67 (q, J=7.17 Hz, 1H), 7.11 (dd, J=7.98,1.73 Hz, 1H), 7.15 (d, J=8.09 Hz, 1H), 7.28 (d, J=1.85 Hz, 1H)

Step 7 (E)-4 Menthyl-pent-2-en-1-ol

(E)-4-Methyl-pent-2-enoic acid methyl ester (16.72 g) was mixed indichloromethane (50 mL). To the reaction solution was added dropwise 1Mdiisobutylaluminum hydride/dichloromethane solution (300 mL) at −78° C.,and the reaction solution was stirred at −78° C. for 1 hour. Thereaction solution was added dropwise to 1.5M aqueous sulfuric acidsolution (350 mL) under ice cooling, and then the mixed solution wasstirred under ice cooling for 1.5 hours. The reaction solution wasextracted with dichloromethane, and the organic layer was washedsequentially with 1M aqueous sulfuric acid solution, water, and aqueoussaturated sodium chloride solution, and dried over magnesium sulfate.After removing magnesium sulfate on a filter, the filtrate wasconcentrated under reduced pressure to give the titled compound indichloromethane solution (73.3 w/w %, 18.81 g).

¹H-NMR (400 MHz, CDCl₃) 1.00 (d, J=6.94 Hz, 6H), 1.25 (s, 1H), 2.31 (td,J=13.58, 6.78 Hz, 1H), 4.09 (d, J=5.78 Hz, 2H), 5.59 (tdd, J=10.63,5.20, 0.89 Hz, 1H), 5.67 (ddt, J=15.26, 6.17, 0.90 Hz, 1H)

Step 8 2-[3-Chloro-4-(3,3-dimethyl-butyl)-phenyl]-propionic acid(E)-4-methyl-pent-2-enyl ester

73.3 w/w % of (E)-4-methyl-pent-2-en-1-ol/dichloromethane solution (5.33g), 2-[3-chloro-4-(3,3-dimethyl-butyl)-phenyl]-propionic acid (10.0 g),and 4-dimethylaminopyridine (1.36 g) were mixed in chloroform (150 mL).To the reaction solution was added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (4.7 g)under ice cooling, and the reaction solution was stirred at roomtemperature overnight. To the reaction solution were added ethyl acetateand 1M hydrochloric acid, which was then extracted with ethyl acetate.The organic layer was washed sequentially with water, aqueous sodiumhydrogen carbonate solution, and aqueous saturated sodium chloridesolution, and dried over magnesium sulfate. After removing magnesiumsulfate on a filter, the filtrate was concentrated under reducedpressure to give the titled compound (13.0 g) as a crude product.

¹H-NMR (400 MHz, CDCl₃) 0.92-1.04 (m, 10H), 1.37-1.51 (m, 5H), 1.56 (s,3H), 2.22-2.33 (m, 1H), 2.59-2.72 (m, 2H), 3.61-3.70 (m, 1H), 4.42-4.60(m, 2H), 5.45 (tt, J=10.87, 3.38 Hz, 1H), 5.65 (dd, J=15.45, 6.52 Hz,1H), 7.08-7.17 (m, 2H), 7.27-7.30 (m, H−1)

Step 92-[3-Chloro-4-(3,3-dimethyl-butyl)-phenyl]-3-isopropyl-2-methyl-pent-4-enoicacid

Diisopropylamine (10.9 mL) was mixed in tetrahydrofuran (130 mL). To thereaction solution was added dropwise 1.64M n-butyllithium/hexanesolution (45.2 mL) at −78° C., and the reaction solution was stirred at−78° C. for 20 minutes. To the reaction solution was added dropwise amixed solution of 2-[3-chloro-4-(3,3-dimethyl-butyl)-phenyl]-propionicacid (E)-4-methyl-pent-2-enyl ester (13.0 g) in tetrahydrofuran (130 mL)over 30 minutes at −78° C., and the reaction solution was stirred underice cooling for 60 minutes. Then thereto was added dropwisechlorotrimethylsilane (9.87 mL) at −78° C., and the reaction solutionwas stirred at −78° C. for 30 minutes, which was then stirred under icecooling for 130 minutes, then at room temperature for 150 minutes. Tothe reaction solution was added 1M hydrochloric acid under ice cooling,which was then extracted with ethyl acetate. The organic layer waswashed sequentially with water and aqueous saturated sodium chloridesolution, and dried over magnesium sulfate. After removing magnesiumsulfate on a filter, the filtrate was concentrated under reducedpressure. The resulted residue was purified through silica gelchromatography (ethyl acetate:hexane=1:30->1:15->1:7) to give the titledcompound (14.49 g).

¹H-NMR (400 MHz, CDCl₃) 0.67 (d, J=6.94 Hz, 2H), 0.74 (d, J=6.70 Hz,2H), 0.83 (d, J=6.70 Hz, 1H), 0.95 (t, J=4.05 Hz, 10H), 1.39-1.47 (m,3H), 1.58 (s, 3H), 2.60-2.65 (m, 2H), 2.79-2.83 (m, 1H), 4.69 (dd,J=16.88, 2.08 Hz, 0.3H), 4.83 (dd, J=10.17, 2.08 Hz, 0.3H), 5.12 (dd,J=7.86, 2.31 Hz, 0.7H), 5.16 (s, 0.7H), 5.31 (dt, J=19.34, 8.44 Hz,0.3H), 5.65-5.74 (m, 0.7H), 7.09 (d, J=8.09 Hz, 0.3H), 7.15 (d, J=8.32Hz, 0.3H), 7.19 (dd, J=8.21, 1.97 Hz, 0.3H), 7.31 (dt, J=12.10, 4.28 Hz,0.3H), 7.43 (d, J=2.08 Hz, 0.3H)

Step 102-Chloro-1-(3,3-dimethyl-butyl)-4-(1-isocyanato-2-isopropyl-1-methyl-but-3-enyl)-benzene

2-[3-Chloro-4-(3,3-dimethyl-butyl)-phenyl]-3-isopropyl-2-methyl-pent-4-enoicacid (12.0 g) and triethylamine (7.2 mL) were mixed in toluene (120 mL).To the reaction solution was added diphenyl phosphoryl azide (11.1 mL),and the reaction solution was stirred at 120° C. for 7.5 hours. Thereaction solution was concentrated under reduced pressure, and theresulted residue was purified through silica gel chromatography (ethylacetate:hexane=1:30) to give the titled compound (9.6 g).

¹H-NMR (400 MHz, CDCl₃) 0.64 (d, J=6.70 Hz, 2H), 0.67 (d, J=6.94 Hz,1H), 0.82 (d, J=6.94 Hz, 1H), 0.84 (d, J=6.70 Hz, 2H), 0.98 (s, 6H),0.98 (s, 3H), 1.46 (m, 2H), 1.62 (s, 1H), 1.74 (s, 2H), 1.99-2.01 (m,0.65H), 2.17-2.20 (m, 1H), 2.35 (brs, 0.35H), 2.64-2.70 (m, 2H),4.88-4.93 (m, 0.65H), 5.12-5.17 (m, 1H), 5.34-5.36 (m, 0.35H), 5.60-5.64(m, 0.65H), 5.81-5.88 (m, 0.35H), 7.15-7.15 (m, 1H), 7.17-7.18 (m, 1H),7.31-7.32 (m, 0.65H), 7.35-7.36 (m, 0.35H)

Step 113-{3-[1-(3-Chloro-4-(3,3-dimethyl-butyl)-phenyl)-2-isopropyl-1-methyl-but-3-enyl]-ureido}-propionicacid ethyl ester

2-Chloro-1-(3,3-dimethyl-butyl)-4-(1-isocyanato-2-isopropyl-1-methyl-but-3-enyl)-benzene(400 mg) and 3-amino-propionic acid ethyl ester hydrochloride (194 mg)were mixed in 1,4-dioxane (4 mL). To the reaction solution was addedtriethylamine (0.18 mL), and the reaction solution was stirred at 60° C.for about 40 minutes. The reaction solution was concentrated underreduced pressure, and the resulted residue was purified through silicagel column chromatography (methanol:chloroform=1:99->2:98->4:96) to givethe titled compound (478 mg).

¹H-NMR (400 MHz, CDCl₃) 0.21-0.26 (m, 0.33H), 0.54-0.60 (m, 0.67H),0.70-0.75 (m, 0.67H), 0.80-0.84 (m, 0.33H), 0.97-0.99 (m, 9H). 1.40-1.53(m, 2H), 1.66-1.69 (m, 2H), 1.79-1.82 (m, 1H), 1.64-1.83 (m, 3H),1.84-2.04 (m, 1H), 2.25-2.45 (m, 2H), 2.61-2.72 (m, 2H), 3.22-3.38 (m,2H), 4.01-4.14 (m, 2H), 4.35-4.59 (m, 1H), 4.87-5.41 (m, 1H), 5.53-5.88(m, 1H), 7.10-7.43 (m, 2H)

Step 123-{4-[3-Chloro-4-(3,3-dimethyl-butyl)-phenyl]-5-isopropyl-4-methyl-2-oxo-3,4-dihydro-2H-pyrimidin-1-yl}-propionicacid ethyl ester

3-{3-[1-(3-Chloro-4-(3,3-dimethyl-butyl)-phenyl)-2-isopropyl-1-methyl-but-3-enyl]-ureido}-propionicacid ethyl ester (478 mg) was mixed in methanol (8 mL). The reactionsolution was stirred at −78° C. for 30 minutes under ozone flow. Thenthe reaction solution was stirred at −78° C. for 3 minutes undernitrogen flow. Then to the reaction solution were added methylsulfide(0.76 mL) at −78° C. and methanol (4 mL) at room temperature. Thereaction solution was concentrated under reduced pressure, and to theresidue was added 2M hydrogen chloride/methanol solution (1 mL), and thereaction solution was stirred at room temperature for 2 hours. Thereaction solution was concentrated under reduced pressure, and theresulted residue was purified through silica gel chromatography(methanol:chloroform=4:96) twice to give the titled compound (191 mg).

¹H-NMR (400 MHz, CDCl3) 0.67-0.72 (m, 3H), 0.96 (s, 9H), 1.00-1.05 (m,3H), 1.22-1.29 (m, 3H), 1.40-1.46 (m, 2H), 1.67 (s, 3H), 1.80-1.89 (m,1H), 2.62-2.69 (m, 4H), 3.74-3.79 (m, 2H), 4.11-4.18 (m, 2H), 4.61 (brs,1H), 5.88 (s, 1H), 7.13-7.17 (m, 1H), 7.20-7.24 (m, 1H), 7.35-7.37 (m,1H)

Step 133-{(S)-4-[3-Chloro-4-(3,3-dimethyl-buty1)-phenyl]-5-isopropyl-4-methyl-2-oxo-3,4-dihydro-2H-pyrimidin-1-yl}-propionicacid ethyl ester

3-{4-[3-Chloro-4-(3,3-dimethyl-butyl)-phenyl]-5-isopropyl-4-methyl-2-oxo-3,4-dihydro-2H-pyrimidin-1-yl}-propionicacid ethyl ester (racemate/191 mg) was purified using a recyclingpreparative chromatograph to give 61 mg as a fraction compound elutedlater (analytical column DAICEL CHIRALPAK IA-3, retention time 7.1minutes) and 58 mg as a fraction compound eluted earlier (analyticalcolumn. DAICEL CHIRALPAK IA-3, retention time 4.9 minutes).

The separation condition by the recycling preparative chromatograph isshown as follows.

-   -   Separation instrument; Recycling preparative chromatograph        LC-9225 NEXT SERIES Japan Analytical Industry Co., Ltd.    -   Column; DAICEL CHIRALPAK IA 2.0 cmφ×25 cm    -   Mobile phase; hexane:2-propanol=90:10    -   Flow rate; 10-0 mL/min    -   Detection; UV (254 nm)

The analytical condition using a chiral column is as follows.

-   -   Measuring instrument; HPLC system Shimadzu Corporation        high-performance liquid chromatograph prominence    -   Column; DAICEL CHIRALPAK IA-3 0.46 cmφ×15 cm    -   Column temperature; 40° C.    -   Mobile phase; hexane:2-propanol=90:10    -   Flow rate; 1.0 mL/min    -   Detection; UV (254 nm)

The ethyl ester compound obtained as a fraction eluted later wasconverted into a carboxylic acid compound in the next step (Step 14,hydrolysis reaction). The retention time and NMR spectrum of thecarboxylic acid compound in a chiral column coincided with those in achiral column of the carboxylic acid compound (S-enantiomer) obtained inthe method using the optically active sulfinamide.

The ester compound obtained as a fraction eluted later was thusestimated as an S-enantiomer

(S-Enantiomer)

¹H-NMR (400 MHz, CDCl₃) 0.67-0.72 (m, 3H), 0.96 (s, 9H), 1.00-1.05 (m,3H), 1.22-1.29 (m, 3H), 1.40-1.46 (m, 2H), 1.67 (s, 3H), 1.80-1.89 (m,1H), 2.62-2.69 (m, 4H), 3.74-3.79 (m, 2H), 4.11-4.18 (m, 2H), 4.61 (brs,1H), 5.88 (s, 1H), 7.13-7.17 (m, 1H), 7.20-7.24 (m, 1H), 7.35-7.37 (m,1H)

(R-Enantiomer)

¹H-NMR (400 MHz, CDCl₃) 0.67-0.72 (m, 3H), 0.96 (s, 9H), 1.00-1.05 (m,3H), 1.22-1.29 (m, 3H), 1.40-1.46 (m, 2H), 1.67 (s, 3H), 1.80-1.89 (m,1H), 2.62-2.69 (m, 4H), 3.74-3.79 (m, 2H), 4.11-4.18 (m, 2H), 4.61 (brs,1H), 5.88 (s, 1H), 7.13-7.17 (m, 1H), 7.20-7.24 (m, 1H), 7.35-7.37 (m,1H)

Step 143-{(S)-4-[3-Chloro-4-(3,3-dimethyl-butyl)-phenyl]-5-isopropyl-4-methyl-2-oxo-3,4-dihydro-2H-pyrimidin-1-yl}-propionicacid

3-{(S)-4-[3-Chloro-4-(3,3-dimethyl-butyl)-pheny1]-5-isopropyl-4-methyl-2-oxo-3,4-dihydro-2H-pyrimidin-1-y}-propionicacid ethyl ester (57 mg) was mixed in methanol (2 mL). To the reactionsolution was added 2M aqueous sodium hydroxide solution (0.25 mL), andthe reaction solution was stirred at 60° C. The reaction solution wasconcentrated under reduced pressure, and then water was added thereto.To the resulted mixed solution was added 2M hydrochloric acid (0.25 mL),which was then stirred at room temperature. The precipitated solid wasfiltered to give the titled compound (49 mg).

The resulted compound was analyzed by a chiral column, and the retentiontime of the resulted titled compound (S-enantiomer) was 9.0 minutes, theoptical purity of which was >99% ee. The analytical condition in thechiral column was as follows.

-   -   Measuring instrument; HPLC system Shimadzu Corporation        high-performance liquid chromatograph prominence    -   Column; DAICEL CHIRALPAK AD-3R 0.46 cmφ×15 cm    -   Column temperature; 40° C.    -   Mobile phase; water:acetonitrile:formic acid=30:70:0.1    -   Flow rate; 0.5 mL/min    -   Detection; UV (220 nm)

Example 86 (The Enantiomer of Example 87)3-{(R)-4-[3-Chloro-4-(3,3-dimethyl-butyl)-phenyl]-5-isopropyl-4-methyl-2-oxo-3,4-dihydro-2H-pyrimidin-1-yl}-propionicacid

3-{(R)-4-[3-Chloro-4-(3,3-dimethyl-butyl)-phenyl]-5-isopropyl-4-methyl-2-oxo-3,4-dihydro-2H-pyrimidin-1-yl}-propionicacid ethyl ester obtained in Example 87 Step 13 was treated according tothe reaction in Example 87 Step 14 to give the titled compound (36 mg).The retention time of the resulted enantiomer (R-enantiomer) was 6.0minutes.

The analytical condition in a chiral column was as follows.

-   -   Measuring instrument; HPLC system Shimadzu Corporation        high-performance liquid chromatograph prominence    -   Column; DAICEL CHIRALPAK AD-3R 0.46 cmφ×15 cm    -   Column temperature; 40° C.    -   Mobile phase; water:acetonitrile:formic acid=30:70:0.1    -   Flow rate; 1.0 mL/min    -   Detection; UV (220 nm)

Example 116 Preparation of3-{(S)-4-[3-chloro-4-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-5-isopropyl-4-methyl-2-oxo-3,4-dihydro-2H-pyrimidin-1-yl}-propionicacid (A Method for Preparation Using an Optically Active Sulfinamide)Step 1 (S)-2-Methyl-propane-2-sulfinic acid[1-(4-bromo-3-chloro-phenyl)-eth-(E)-ylidene]-amide

1-(4-Bromo-3-chloro-phenyl)-ethanone (20 g) prepared according toExample 87 (a method for preparation using an optically activesulfinamide) Steps 1 to 2 and (S)-(−)-2-methyl-propane-2-sulfinic acidamide (11.4 g) were mixed in cyclopentylmethyl ether (100 mL). To thereaction solution was added tetraethyl orthotitanate (23.3 mL), and thereaction solution was stirred at 100° C. for 5 hours. To the reactionsolution was added 25 w/w % aqueous citric acid solution under icecooling, and the mixed solution was stirred at room temperature. Afterremoving an insoluble on a filter, the filtrate was extracted withtoluene. The organic layer was washed sequentially with water andaqueous saturated sodium chloride solution, and then concentrated underreduced pressure. The resulted residue was purified through silica gelcolumn chromatography (ethyl acetate:hexane=1:20->1:10->1:5) to give thetitled compound (23 g).

¹H-NMR (400 MHz, CDCl₃) 1.30 (s, 9H), 2.72 (s, 3H), 7.56-7.61 (m, 1H),7.66 (d, J=8.55 Hz, 1H), 7.91 (d, J=2.08 Hz, 1H)

Step 2(R)-3-(4-Bromo-3-chloro-phenyl)-2-isopropy1-3-((S)-2-methyl-propane-2-sulfinylamino)-butanoicacid methyl ester

Diisopropylamine (21.1 mL) was mixed in THE (138 mL) under argon gas. Tothe reaction solution was added dropwise 1.63M n-butyllithium/hexanesolution (88 mL) at −78° C., and the reaction solution was stirred at−78° C. for 20 minutes. To the reaction solution was added dropwise3-methyl-butanoic acid methyl ester (18 mL), and the reaction solutionwas stirred at −78° C. for 30 minutes. To the reaction solution wereadded dropwise 1M chloro titanium (IV) triisopropoxide/hexane solution(100 mL) and then a mixed solution of chloro titanium (IV)triisopropoxide (48.7 g) in tetrahydrofuran (80 mL), and the reactionsolution was stirred at −78° C. for 30 minutes. To the reaction solutionwas added dropwise a mixed solution of (S)-2-methyl-propane-2-sulfinicacid [1-(4-bromo-3-chloro-phenyl)-eth-(E)-ylidene]-amide (23 g) in THF(138 mL), and the reaction solution was stirred at −78° C. for 75minutes and then at −45° C. for 2 hours. The reaction solution was addeddropwise saturated aqueous Rochelle salt solution. The mixed solutionwas extracted with ethyl acetate. The organic layer was washedsequentially with water and aqueous saturated sodium chloride solution,and then dried over sodium sulfate. After removing sodium sulfate on afilter, the filtrate was concentrated under reduced pressure. Theresulted residue was purified through silica gel column chromatography(ethyl acetate:hexane=1:10) to give the titled compound (16 g) as amixture of diastereomers generated by the isopropyl group at α-positionof ester (d.r.=72: 28).

¹H-NMR (400 MHz, CDCl₃) 0.75-1.01 (m, 6H), 1.25 (s, 6H), 1.33 (s, 3H),1.87-1.88 (m, 3H), 2.04-2.12 (m, 1H), 2.46 (d, J=4.11 Hz, 0.3H), 2.80(d, J=3.86 Hz, 0.7H), 3.60 (t, J=6.64 Hz, 2H), 3.71 (s, 1H), 5.13 (s,0.7H), 5.42 (s, 0.3H), 7.14-7.22 (m, 1H), 7.52-7.56 (m, 1H), 7.57-7.59(m, 1H)

Step 3 (S)-2-Methyl-propane-2-sulfinic acid[(R)-1-(4-bromo-3-chloro-phenyl)-2-hydroxymethyl-1,3-dimethyl-butyl]amide

(R)-3-(4-Bromo-3-chloro-phenyl)-2-isopropyl-3-((S)-2-methyl-propane-2-sulfinylamino)-butanoicacid methyl ester (16 g) was mixed in toluene (160 mL) under argon gas.To the reaction solution was added dropwise 1.01M diisobutylaluminumhydride/toluene solution (140 mL) at −78° C., and the reaction solutionwas stirred at −78° C. for 30 minutes, and then gradually warmed to 0°C., and then stirred for 1 hour. To the reaction solution were addeddropwise methanol and then aqueous Rochelle salt solution under icecooling, and then the mixed solution was extracted with ethyl acetate.The organic layer was washed sequentially with water and aqueoussaturated sodium chloride solution, and then dried over sodium sulfate.After removing sodium sulfate on a filter, the filtrate was concentratedunder reduced pressure. The resulted residue was purified through silicagel column chromatography (ethyl acetate:hexane=1:5->1:3->1:1, thenethyl acetate only, then methanol:chloroform=1:20) to give the titledcompound (11.5 g).

¹H-NMR (400 MHz, CDCl₃) 0-66-0.85 (m, 6H), 1.13 (s, 7H), 1.29 (s, 2H),1.69-1.81 (m, 2H), 1.89-2.00 (m, 3H), 2.01-2.12 (m, 1H), 3.83-4.12 (m,2H), 5.06-5.28 (m, 1H), 6.81-6.93 (m, 1H), 7.12-7.23 (m, 1H), 7.50-7.62(m, 2H)

Step 4 (R)-3-Amino-3-(4-bromo-3-chloro-phenyl)-2-isopropyl-butan-1-ol

(S)-2-Methyl-propane-2-sulfinic acid[(R)-1-(4-bromo-3-chloro-phenyl)-2-hydroxymethyl-1,3-dimethyl-butyl]amide(11.5 g) was mixed in methanol (66 mL). To the reaction solution wasadded dropwise 2M hydrogen chloride/methanol solution (54 mL) under icecooling, and the reaction solution was left to stand at room temperatureovernight. The reaction solution was concentrated under reducedpressure, and aqueous sodium carbonate solution was added to the residueso that the aqueous layer was adjusted to pH 10, and then the reactionsolution was extracted with chloroform. The organic layer was washedsequentially with water and aqueous saturated sodium chloride solution,and then dried over sodium sulfate. After removing sodium sulfate on afilter, the filtrate was concentrated under reduced pressure to give thetitled compound (14 g) as a crude product.

¹H-NMR (400 MHz, CDCl₃) 0.66-0.89 (m, 6H), 1.34-1.49 (m, 1H), 1.58-1.61(m, 3H), 1.62-1.76 (m, 1H), 1.83-1.88 (m, 1H), 3.65-3.72 (m, 1H),3.87-4.00 (m, 1H), 7.12-7.25 (m, 3H), 7.48-7.55 (m, 1H), 7.55-7.63 (m,1H)

Step 53-{3-[(R)-1-(4-Bromo-3-chloro-phenyl)-2-hydroxymethyl-1,3-dimethyl-butyl]-ureidol}-propionicacid ethyl ester

(R)-3-Amino-3-(4-bromo-3-chloro-phenyl)-2-isopropyl-butan-1-ol (14 g)was mixed in tetrahydrofuran (50 mL). To the reaction solution was addeda mixed solution of 3-isocyanate-propionic acid ethyl ester (3.56 mL) intetrahydrofuran (50 mL) under ice cooling, and the reaction solution wasstirred under ice cooling for 1.5 hours. To the reaction solution wasadded water, which was then extracted with ethyl acetate. The organiclayer was washed sequentially with 0.1M hydrochloric acid, water, andaqueous saturated sodium chloride solution, and then dried over sodiumsulfate. After removing sodium sulfate on a filter, the filtrate wasconcentrated under reduced pressure. The resulted residue was purifiedthrough silica gel column chromatography (ethylacetate:hexane=1:10->1:5->1:3->1:1, then methanol:chloroform=1:20) togive the titled compound (13.7 g).

¹H-NMR (400 MHz, CDCl₃) 0.26-0.80 (m, 3H), 0.80-0.97 (m, 3H), 1.23-1.31(m, 3H), 1.46-1-55 (m, 1H), 1.64-1.71 (m, 1H), 1.79-1.90 (m, 3H),2.38-2.48 (m, 2H), 3.28-3.39 (m, 2H), 3.76-3.85 (m, 1H), 3.88-3.99 (m,1H), 4.08-4.18 (m, 2H), 4.55-4.71 (m, 1H), 7.06-7.13 (m, 1H), 7.14-7.22(m, 1H), 7.43-7.58 (m, 2H)

Step 63-[(S)-4-(4-Bromo-3-chloro-pheny1)-5-isopropyl-4-methyl-2-oxo-3,4-dihydro-2H-pyrimidin-1-yl]-propionicacid ethyl ester

3-{3-[(R)-1-(4-Bromo-3-chloro-phenyl)-2-hydroxymethyl-1,3-dimethyl-butyl]-ureido}-propionicacid ethyl ester (9.49 g) and iodobenzene diacetate (7.26 g) were mixedin dichloromethane (95 mL). To the reaction solution was added2,2,6,6-tetramethylpiperidine 1-oxyl free radical (319 mg) under icecooling, and the reaction solution was stirred at room temperature for3.5 hours. To the reaction solution was added TFA (6.1 mL) under icecooling, and the reaction solution was stirred at room temperature for3.5 hours. To the reaction solution were added 20 w/w % aqueous sodiumsulfite solution and 25 w/w % aqueous potassium hydrogen carbonatesolution, and then the mixed solution was extracted with chloroform. Theorganic layer was washed sequentially with 25 w/w % aqueous potassiumhydrogen carbonate solution and aqueous saturated sodium chloridesolution, and then dried over magnesium sulfate. After removingmagnesium sulfate on a filter, the filtrate was concentrated underreduced pressure. The resulted residue was purified through silica gelcolumn chromatography (ethyl acetate:hexane=1:6->1:3->1:2) to give thetitled compound (7.77 g).

¹H-NMR (400 MHz, CDCl₃) 0.68-0.74 (m, 3H), 1.00-1.07 (m, 3H), 1.26 (s,3H), 1.68 (s, 3H), 1.80-1.89 (m, 1H), 2.60-2.67 (m, 2H), 3.72-3.78 (m,2H), 4.08-4.19 (m, 2H), 4.82 (brs, 1H), 5.91 (s, 1H), 7.15-7.21 (m, 1H),7.47-7.51 (m, 1H), 7.53-7.58 (m, 1H)

Step 73-{(S)-4-[3-Chloro-4-(4,4-dimethyl-1-cyclohex-1-enyl)-phenyl]-5-isopropyl-4-methyl-2-oxo-3,4-dihydro-2H-pyrimidin-1-yl}-propionicacid ethyl ester

3-[(S)-4-(4-Bromo-3-chloro-phenyl)-5-isopropyl-4-methyl-2-oxo-3,4-dihydro-2H-pyrimidin-1-yl]-propionicacid ethyl ester (58.1 g) prepared according to Example 116 (a methodfor preparation using an optically active sulfinamide) Steps 1 to 6,3-[(S)-4-(4-bromo-3-chloro-phenyl)-5-isopropyl-4-methyl-2-oxo-3,4-dihydro-2H-pyrimidin-1-yl]-propionicacid ethyl ester obtained in the previous step 6 (2.9 g),2-(4,4-dimethyl-1-cyclohexenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane(48.9 g), and tripotassium phosphate (87.7 g) were mixed in1,2-dimethoxyethane (777 mL) and water (194 mL) under argon gas. To thereaction solution was added bis(triphenylphosphine)palladium (II)dichloride (5.6 g), and the reaction solution was stirred at 100° C. for4 hours. To the reaction solution was added ethyl acetate at roomtemperature, and then an insoluble was removed on a filter. The filtratewas extracted with ethyl acetate, washed with aqueous saturated sodiumchloride solution, and then dried over sodium sulfate. After removingsodium sulfate on a filter, the filtrate was concentrated under reducedpressure. The resulted residue was purified twice through silica gelchromatography to give the titled compound (48.3 g).

¹H-NMR (400 MHz, CDCl₃) 0.73 (d, J=6.76 Hz, 3H), 1.00 (s, 6H), 1.05 (d,J=7.00 Hz, 3H), 1.27 (t, J=7.00 Hz, 2H), 1.50 (t, J=6.52 Hz, 2H), 1.69(s, 3H), 1.85-1.92 (m, 1H), 1.95-1.97 (m, 2H), 2.28-2.32 (m, 2H), 2.67(t, J=6.64 Hz, 2H), 3.78 (t, J=6.64 Hz, 2H), 4.13-4.19 (m, 2H), 4.62 (s,1H), 5.58-5.61 (m, 1H), 5.91 (s, 1H), 7.11 (d, J=7.97 Hz, 1H), 7.25 (dd,J=7.97, 1.93 Hz, 1H), 7.38 (d, J=1.93 Hz, 1H)

Step 83-{(S)-4-[3-Chloro-4-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-5-isopropyl-4-methyl-2-oxo-3,4-dihydro-2H-pyrindin-1-yl}-propionicacid

3-{(S)-4-[3-Chloro-4-(4,4-dimethyl-1-cyclohex-1-enyl)-phenyl]-5-isopropyl-4-methyl-2-oxo-3,4-dihydro-2H-pyrimidin-1-yl}-propionicacid ethyl ester (48.3 g) was mixed in ethanol (480 mL). To the reactionsolution was added 4M aqueous sodium hydroxide solution (51 mL) underice cooling, and the reaction solution was stirred at room temperatureovernight. The reaction solution was concentrated under reducedpressure, and then thereto was added water (960 mL). To the reactionsolution was added 2M hydrochloric acid (102 mL) under ice cooling, andthe reaction solution was stirred under ice cooling for 3 hours. Theprecipitated solid was filtered to give the titled compound (41 g) as acrystal. The specific optical rotation of the resulted compound was[α]_(D) ²⁵=+106.10 (c=1.00, methanol). The melting point of the resultedcrystal was 90-95° C.

The resulted compound was analyzed using a chiral column, and theretention time of the resulted titled compound (S-enantiomer) was 9.2minutes, the optical purity of which was >99% ee.

The analytical condition in the chiral column is shown as follows.

-   -   Measuring instrument; HPLC system Shimadzu Corporation        high-performance liquid chromatograph prominence    -   Column; DAICEL CHIRALPAK AD-3R 0-46 cmφ×15 cm    -   Column temperature; 40° C.    -   Mobile phase; water:acetonitrile:formic acid=30:70:0.1    -   Flow rate; 1.0 mL/min    -   Detection; UV (220 nm)

Example 116 Preparation of3-{(S)-4-[3-chloro-4-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-5-isopropyl-4-methyl-2-oxo-3,4-dihydro-2H-pyrimidin-1-yl}-propionicacid (A Method for Preparation Using Cleisen Reaction) Step 14-Bromo-3-chloro-N-methoxy-N-methylbenzamide

4-Bromo-3-chlorobenzoic acid (25.0 g), N,O-dimethylhydroxylaminehydrochloride (12.4 g), 1-hydroxybenzotriazolemonohydrate (19.5 g), andtriethylamine (22.2 mL) were mixed in N,N-dimethylformamide (100 ml). Tothe reaction solution was added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (24.4 g)under ice cooling, and the reaction solution was stirred at roomtemperature overnight. To the reaction solution was added 5 w/v %aqueous sodium hydrogen carbonate solution, which was then extractedwith ethyl acetate. The organic layer was washed sequentially with waterand aqueous saturated sodium chloride solution, and dried over magnesiumsulfate. After removing magnesium sulfate on a filter, the filtrate wasconcentrated under reduced pressure to give the titled compound (31 g)as a crude product.

¹H-NMR (400 MHz, CDCl₃) 3.36 (d, J=1.16 Hz, 3H), 3.55 (d, J=0.92 Hz,3H), 7.47 (dt, J=8.17, 1.50 Hz, 1H), 7.66 (dd, 3=8.32, 1.16 Hz, 1H),7.81 (t, J=1.50 Hz, 1H)

Step 2 1(4-Bromo-3-chloro-phenyl)-propan-1-one

4-Bromo-3-chloro-N-methoxy-N-methylbenzamide (31 g) was mixed intetrahydrofuran (60 mL). To the reaction solution was added dropwise0.97M ethylmagnesium bromide/tetrahydrofuran solution (141 mL) under icecooling, and the reaction solution was stirred at room temperature for1.5 hours. To the reaction solution was added 2M hydrochloric acid (140mL) under ice cooling, which was then extracted with toluene. Theorganic layer was washed sequentially with water and aqueous saturatedsodium chloride solution, and dried over magnesium sulfate. Afterremoving magnesium sulfate on a filter, the filtrate was concentratedunder reduced pressure to give the titled compound (26.80 g) as a crudeproduct.

¹H-NMR (400 MHz, CDCl₃) 1.22 (t, J=7.17 Hz, 3H), 2.96 (q, J=7.17 Hz,2H), 7.68 (dd, J=8.44, 1.97 Hz, 1H), 7.72 (d, J=8.32 Hz, 1H), 8.02 (d,J=1.85 Hz, 1H)

Step 3 2-(4-Bromo-3-chloro-phenyl)-propionic acid methyl ester

1-(4-Bromo-3-chloro-phenyl)-propan-1-one (26.80 g) and iodobenzenediacetate (36.9 g) were mixed in trimethyl orthoformate (250 mL). To thereaction solution was slowly added concentrated sulfuric acid (11.1 mL)under water cooling, and the reaction solution was stirred at 60° C. for3 hours. To the reaction solution was added water, which was thenextracted with ethyl acetate. The organic layer was washed sequentiallywith aqueous sodium sulfite solution, water, and aqueous saturatedsodium chloride solution, and dried over magnesium sulfate. Afterremoving magnesium sulfate on a filter, the filtrate was concentratedunder reduced pressure to give the titled compound (55.3 g) as a crudeproduct.

¹H-NMR (400 MHz, CDCl₃) 1.48 (d, J=7.17 Hz, 3H), 3.23 (dd, J=7.40, 0.46Hz, 1H), 3.67 (d, J=0.46 Hz, 3H), 7.06 (dd, J=8.32, 2.08 Hz, 1H), 7.40(d, J=2.08 Hz, 1H), 7.55 (d, J=8.32 Hz, 1H)

Step 4 2-(4-Bromo-3-chloro-phenyl)-propionic acid

2-(4-Bromo-3-chloro-phenyl)-propionic acid methyl ester (55.3 g) wasmixed in tetrahydrofuran (100 mL) and methanol (100 mL). To the reactionsolution was added 2M aqueous sodium hydroxide solution (150 mL), andthe reaction solution was stirred at 60° C. for 1.5 hours. To thereaction solution was added 2M aqueous sodium hydroxide solution (50mL), and the reaction solution was further stirred for 3.5 hours. Thereaction solution was concentrated under reduced pressure, and to theresulted residue was added hexane (150 mL), which was separated. Theaqueous layer was washed again with hexane (150 mL), and then theretowas added 2M hydrochloric acid (200 mL), which was extracted with ethylacetate. The organic layer was washed sequentially with water andaqueous saturated sodium chloride solution, and dried over magnesiumsulfate. After removing magnesium sulfate on a filter, a mixed solutionwhich toluene was added to the filtrate was concentrated under reducedpressure to give the titled compound (21.6 g) as a crude product.

¹H-NMR (400 MHz, CDCl₃) 1.51 (d, J=7.17, 3H), 3.70 (q, J=7.17 Hz, 1H),7.08 (dd, J=8.21, 2.20 Hz, 1H), 7.42 (d, J=2.08 Hz, 1H), 7.57 (t, J=6.01Hz, 1H), 10.63 (s, 1H)

Step 5 (E)-4-Methyl-pent-2-en-1-o1

(E)-4-methyl-pent-2-enoic acid methyl ester (20.7 g) was mixed indichloromethane (50 mL). To the reaction solution was added dropwise 1Mdiisobutylaluminum hydride/dichloromethane solution (300 mL) at −78° C.,and the reaction solution was stirred at −78° C. for 1 hour. To thereaction solution was added methanol (45 mL), and then the reactionsolution was warmed to room temperature. The reaction solution was addeddropwise to 1M aqueous sulfuric acid solution (150 mL), and thenextracted with dichloromethane. The organic layer was washed withaqueous saturated sodium chloride solution and dried over sodiumsulfate. After removing sodium sulfate on a filter, the filtrate wasconcentrated under reduced pressure to give the titled compound indichloromethane solution (35.1 w/w %, 57.3 g).

¹H-NMR (400 MHz, CDCl₃) 1.00 (d, J=6.94 Hz, 6H), 1.25 (s, 1H), 2.31 (td,J=13.58, 6.78 Hz, 1H), 4.09 (d, J=5.78 Hz, 2H), 5.59 (tdd, J=10.63,5.20, 0.89 Hz, 1H), 5.67 (ddt, J=15.26, 6.17, 0.90 Hz, 1H)

Step 6 2-(4-Bromo-3-chloro-phenyl)-propionic acid(E)-4-methyl-pent-2-enyl ester

35.1 w/w % of (E)-4-methyl-pent-2-en-1-ol/dichloromethane solution (28.8g) and 4-dimethylaminopyridine (11.4 g) were mixed in dichloromethane(200 mL). To the reaction solution was added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (17.9 g)under ice cooling, and the reaction solution was stirred for 30 minutes.To the reaction solution was added a mixed solution of2-(4-bromo-3-chloro-phenyl)-propionic acid (22.0 g) in dichloromethane(100 mL), and the reaction solution was stirred at room temperatureovernight. To the reaction solution was added water (200 mL), which wasthen extracted with chloroform. The organic layer was washedsequentially with 1M aqueous hydrochloric acid solution, 5 w/v % aqueoussodium hydrogen carbonate solution, water, and aqueous saturated sodiumchloride solution, and dried over magnesium sulfate. After removingmagnesium sulfate on a filter, the filtrate was concentrated underreduced pressure. The resulted residue was purified through silica gelchromatography (toluene:hexane=1:2) to give the titled compound (20.8g).

¹H-NMR (400 MHz, CDCl₃) 0.97 (d, J=6.47 Hz, 6H), 1.48 (d, J=7.17 Hz,3H), 2.28 (td, 3=13.35, 6.70 Hz, 1H), 3.66 (q, 3=7.24 Hz, 1H), 4.51 (dd,J=6.59, 3.35 Hz, 2H), 5.44 (dtd, J=15.45, 6.36, 1.35 Hz, 1H), 5.66 (ddt,J=15.49, 6.47, 1.18 Hz, 1H), 7.07 (dd, J=8.32, 2.08 Hz, 1H), 7.41 (d,J=2.08 Hz, 1H), 7.55 (d, J=8.09 Hz, 1H)

Step 7 2-(4-Bromo-3-chloro-phenyl)-3-isopropyl-2-methyl-pent-4-enoicacid

2-(4-Bromo-3-chloro-phenyl)-propionic acid (E)-4-methyl-pent-2-enylester (17.5 g) was mixed in tetrahydrofuran (200 mL). To the reactionsolution was added dropwise 1.17M lithiumhexamethyldisilazane/tetrahydrofuran solution (45.3 mL) at −41° C., andthe reaction solution was stirred at −41° C. for 1 hour. To the reactionsolution was added dropwise chlorotrimethylsilane (118 mL), and then thereaction solution was stirred at −41° C. for 30 minutes and then stirredat room temperature overnight. To the reaction solution was added 1Maqueous hydrochloric acid solution, which was then extracted with ethylacetate. The organic layer was concentrated under reduced pressure togive the titled compound (18.0 g) as a crude product.

¹H-NMR (400 MHz, CDCl₃) 0.71 (d, J=6.70 Hz, 2.01H), 0.76 (d, J=6.70 Hz,2.01H), 0.86 (d, J=6.70 Hz, 0.99H), 0.96 (d, J=6.70 Hz, 0.99H), 1.57(ddd, J=13.47, 6.65, 3.99 Hz, 0.67H), 1.60 (s, 2.01H), 1.61 (s, 0.99H),1.78 (ddd, J=13.47, 6.65, 3.99 Hz, 0.33H), 2.78 (dd, J=9.13, 2.89 Hz,0.33H), 2.81 (dd, J=10.06, 2.66 Hz, 0.67H), 4.71 (dd, J=16.88, 1.62 Hz,0.33H), 4.87 (dd, J=10.17, 2.08 Hz, 0.33H), 5.15 (dd, J=13.87, 2.31 Hz,0.67H), 5.18 (dd, J=7.28. 2.20 Hz, 0.67H), 5.31 (dt, J=19.42, 8.50 Hz,0.3314), 5.70 (dt, J=19.19, 8.38 Hz, 0.67H), 7.17 (dd, J=8.32, 2.31 Hz,0.33H), 7.28 (dd, J=8.67, 2.43 Hz, 0.67H). 7.48 (d, J=2.31 Hz, 0.33H),7.50 (d, J=8.55 Hz, 0.33H), 7.57 (d, J=8.55 Hz, 0.67H), 7.59 (d, J=2.31Hz, 0.67H), 10.3 (s, 1H)

Step 81-Bromo-2-chloro-4-(1-isocyanato-2-isopropyl-1-methyl-but-3-enyl)-benzene

2-(4-Bromo-3-chloro-phenyl)-3-isopropyl-2-methyl-pent-4-enoic acid (18.0g) and triethylamine (10.6 mL) were mixed in toluene (300 mL). To thereaction solution was added diphenyl phosphoryl azide (16.3 mL), and thereaction solution was stirred at 70° C. for 2 hours. The reactionsolution was concentrated under reduced pressure, and the resultedresidue was purified through silica gel chromatography(chloroform:hexane=1:4) to give the titled compound (15.5 g).

¹H-NMR (400 MHz, CDCl₃) 0.69 (d, J=6.47 Hz, 1.05H), 0.70 (d, J=6.94 Hz,1.95H), 0.83 (d, J=6.94 Hz, 1.05H), 0.86 (d, J=6.94 Hz, 1.95H),1.40-1.48 (m, 0.35H), 1.63 (s, 1.05H), 1.76 (s, 1.95H), 1.99-2.06 (m,0.65H), 2.16 (dd, J=10.17, 2.31 Hz, 0.65H), 2.20 (dd, J=9.94, 2.54 Hz,0.35H), 4.88 (dd, J=16.99, 1.97 Hz, 0.65H), 5.13 (dd, J=10.29, 1.97 Hz,0.65H), 5.18 (dd, J=16.88, 2.08 Hz, 0.35H), 5.38 (dd, J=10.29, 1.97 Hz,0.35H), 5.60 (dt, J=19.27, 8.50 Hz, 0.65H), 5.84 (dt, J=19.03, 8.44 Hz,0.35H), 7.10 (dd, J=8.55, 2.31 Hz, 0.65H), 7.14 (dd, J=8.55, 2.31 Hz,0.35H), 7.45 (d, J=2.31 Hz, 0.65H), 7.51 (d, J=−2.31 Hz, 0.35H), 7.55(d, J=8.32 Hz, 0.65H), 7.59 (d, J=8.32 Hz, 0.35H)

Step 93-{3-[1-(4-Bromo-3-chloro-phenyl)-2-isopropyl-1-methyl-but-3-enyl]-ureido}-propionicacid ethyl ester

1-Bromo-2-chloro-4-(1-isocyanato-2-isopropyl-1-methyl-but-3-enyl)-benzene(13.76 g) and triethylamine (11.2 mL) were mixed in tetrahydrofuran (100mL). To the reaction solution was added 3-amino-propionic acid ethylester hydrochloride (7.4 g) under ice cooling, and the reaction solutionwas stirred at room temperature overnight. To the reaction solution wasadded 1M aqueous hydrochloric acid solution (100 mL), which was thenextracted with ethyl acetate. The organic layer was washed sequentiallywith 1M hydrochloric acid, 5 w/v % aqueous sodium hydrogen carbonatesolution, water, and aqueous saturated sodium chloride solution, anddried over magnesium sulfate. The organic layer was concentrated underreduced pressure to give the titled compound (18.5 g) as a crudeproduct.

¹H-NMR (400 MHz, CDCl₃) 0.32 (d, J=6.70 Hz, 1.02H), 0.59 (d, J=6.70 Hz,1.98H), 0.76 (d, J=6.70 Hz, 1.98H), 0.84 (d, J=6.94 Hz, 1.02H), 1.25 (t,J=7.05 Hz, 1.98H), 1.25 (t, J=7.17 Hz, 1.02H), 1.45-1.53 (m, 1H), 1.71(s, 1.98H), 1.83 (s, 1.02H), 1.98 (dd, J=10.52, 1.97 Hz, 0.66H), 1-99(dd, J=10.52, 1.50 Hz, 0.34H), 2.38 (td, J=5.84, 1.77 Hz, 1.32H), 2.42(t, J=5.90 Hz, 0.68H), 3.25-3.41 (m, 2H), 4.11 (q, J=7.17 Hz 1.32H),4.11 (q, J=7.17 Hz, 0.68H), 4.57 (t, J=6.01 Hz, 0.66H), 4.66 (t, J=6.13Hz, 0.34H), 4.93 (s, 1H), 5.07 (dd, J=16.88, 1.85 Hz, 0.34H), 5.22 (dd,J=7.34, 2.54 Hz, 0.66H), 5.26 (dd, J=10.87, 2.31 Hz, 0.34H), 5.37 (dd,J=10.06, 1.97 Hz, 0.66H), 5.59 (dt, J=19.50, 8.44 Hz, 0.34H), 5.79 (dt,J=19.42, 8.50 Hz, 0.66H), 7.09 (dd, J=8.55, 2.31 Hz, 0.34H), 7.20 (dd,J=8.32, 2.31 Hz, 0.66H), 7.41 (d, J=2.31 Hz, 0.34H), 7.51 (d, J=2.31 Hz,0.66H), 7.53 (d, J=8.32 Hz, 0.34H), 7.56 (d, J=8.32 Hz, 0.66H)

Step 103-[4-(4-Bromo-3-chloro-phenyl)-5-isopropyl-4-methyl-2-oxo-3,4-dihydro-2H-pyrimidin-1-y1]-propionicacid ethyl ester

3-{3-[1-(4-Bromo-3-chloro-phenyl)-2-isopropyl-1-methyl-but-3-enyl]-ureido}-propionicacid ethyl ester (18.5 g) was mixed in methanol (100 mL) anddichloromethane (50 mL). The reaction solution was stirred at −78° C.for 3 hours under ozone flow. The reaction solution was then stirred at−78° C. for 30 minutes under nitrogen flow. To the reaction solution wasadded methylsulfide (15 mL) at −78° C., and the reaction solution waswarmed to room temperature. To the reaction solution was added ethanol(50 mL), and the mixed solution was concentrated under reduced pressure.To the resulted residue was added 2M hydrogen chloride/ethanol solution(50 mL), and the reaction solution was stirred at room temperature for 1hour. The reaction solution was concentrated under reduced pressure, andthe resulted residue was purified through silica gel chromatography(ethyl acetate:chloroform=1:4) and then recrystallized from a mixedsolution of hexane-diisopropylether (1:1) to give the titled compound(6.19 g).

¹H-NMR (400 MHz, CDCl₃) 0.68-0.74 (m, 3H), 1.00-1.07 (m, 3H), 1.26 (s,3H), 1.68 (s, 3H), 1.80-1.89 (m, 1H), 2.60-2.67 (m, 2H), 3.72-3.78 (m,2H), 4.08-4.19 (m, 2H), 4.82 (brs, 1H), 5.91 (s, 1H), 7.15-7.21 (m, 1H),7.47-7.51 (m, 1H), 7.53-7.58 (m, 1H)

Step 113-{4-[3-Chloro-4-(4,4-dimethyl-1-cyclohex-1-enyl)-phenyl]-5-isopropyl-4-methyl-2-oxo-3,4-dihydro-2H-pyrimidin-1-yl}-propionicacid ethyl ester

3-[4-(4-Brorno-3-chloro-phenyl)-5-isopropyl-4-methyl-2-oxo-3,4-dihydro-2H-pyrimidin-1-y1]-propionicacid ethyl ester (200 mg),2-(4,4-dimethyl-1-cyclohexenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane(160 mg) and tripotassium phosphate (287 mg) were mixed in1,2-dimethoxyethane (4 mL) and water (1 mL) under argon gas. To thereaction solution was added bis(triphenylphosphine)palladium (II)dichloride (16 mg), and the reaction solution was stirred at 100° C.overnight. To the reaction solution was added ethyl acetate at roomtemperature, and then an insoluble was removed on a filter. The filtratewas washed sequentially with water and aqueous saturated sodium chloridesolution, and then dried over sodium sulfate. After removing sodiumsulfate on a filter, the filtrate was concentrated under reducedpressure. The resulted residue was purified through silica gelchromatography (ethyl acetate:hexane=1:3), followed by thin layer silicagel chromatography (methanol:chloroform=1: 30) to give the titledcompound (180 mg).

¹H-NMR (400 MHz, CDCl₃) 0.73 (d, J=6.76 Hz, 3H), 1.00 (s, 6H), 1.05 (d,J=7.00 Hz, 3H), 1.27 (t, J=7.00 Hz, 2H), 1.50 (t, J=6.52 Hz, 2H), 1.69(s, 3H), 1.85-1.92 (m, 1H), 1.95-1.97 (m, 2H), 2.28-2.32 (m, 2H), 2.67(t, J=6.64 Hz, 2H), 3.78 (t, J=6.64 Hz, 2H), 4.13-4.19 (m, 2H), 4.62 (s,1H), 5.58-5.61 (m, 1H), 5.91 (s, 1H), 7.11 (d, J=7.97 Hz, 1H), 7.25 (dd,J=7.97, 1.93 Hz, 1H), 7.38 (d, J=1.93 Hz, 1H)

Step 123-{(S)-4-[3-Chloro-4-(4,4-dimethyl-1-cyclohex-1-enyl)-phenyl]-5-isopropyl-4-methyl-2-oxo-3,4-dihydro-2H-pyrimidin-1-yl}-propionicacid ethyl ester

3-{4-[3-Chloro-4-(4,4-dimethyl-1-cyclohex-1-enyl)-phenyl]-5-isopropyl-4-methyl-2-oxo-3,4-dihydro-2H-pyrimidin-1-propionicacid ethyl ester (racemate/190 mg) was purified with recyclingpreparative chromatograph to give 71 mg as a fraction compound elutedlater (analytical column DAICEL CHIRALPAK IA-3, retention time 6.4minutes) and 75 mg as a fraction compound eluted earlier (analyticalcolumn DAICEL CHIRALPAK IA-3, retention time 4.1 minutes).

The separation condition in the recycling preparative chromatograph isshown as follows.

-   -   Separation instrument; Recycling preparative chromatograph        LC-9225 NEXT SERIES Japan Analytical Industry Co., Ltd.    -   Column; DAICEL CHIRALPAK IA 2.0 cmφ×25 cm    -   Mobile phase; hexane:2-propanol=90:10    -   Flow rate; 10.0 mL/min.    -   Detection; UV (254 nm)

The analytical condition in a chiral column is shown as follows.

-   -   Measuring instrument; HPLC system Shimadzu Corporation        high-performance liquid chromatograph prominence    -   Column; DAICEL CHIRALPAK IA-3 0.46 cmφ×15 cm    -   Column temperature; 40° C.    -   Mobile phase; hexane: 2-propanol=90:10    -   Flow rate; 1.0 mL/min    -   Detection; UV (254 nm)

The retention time of the compound obtained in the next step byhydrolysis of the compound as a fraction eluted later in a chiral columncoincided with that in the chiral column of the compound obtained by themethod using the optically active sulfinamide in Example 116 Step 8. Thecompound obtained as a fraction eluted later was thus estimated as anS-enantiomer.

Step 133-{(S)-4-[3-Chloro-4-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-5-isopropyl-4-methyl-2-oxo-3,4-dihydro-2H-pyrimidin-1-yl}-propionic,acid

3-{(S)-4[3-Chloro-4-(4,4-dimethyl-1-cyclohex-1-enyl)-phenyl]-5-isopropyl-4-methyl-2-oxo-3,4-dihydro-2H-pyrimidin-1-yl}-propionicacid ethyl ester (25 mg) was mixed in tetrahydrofuran (0.5 mL) andmethanol (1 mL), and thereto was added 1M aqueous sodium hydroxidesolution (0.16 mL) at room temperature. The reaction solution wasstirred at 50° C. for 8 hours. The reaction solution was concentratedunder reduced pressure, and then thereto was added water. To the mixedsolution was added 1M hydrochloric acid (0.2 mL) under ice cooling, andthen the mixed solution was stirred at room temperature. Theprecipitated solid was filtered to give the titled compound (19 mg). Theresulted compound was analyzed by a chiral column, and the retentiontime of the resulted titled compound (S-enantiomer) was 9.2 minutes, theoptical purity of which was >99% ee.

The analytical condition in the chiral column is shown as follows.

-   -   Measuring instrument; HPLC system Shimadzu Corporation        high-performance liquid chromatograph prominence    -   Column; DAICEL CHIRALPAK AD-3R 0.46 cmφ×15 cm    -   Column temperature; 40° C.    -   Mobile phase; water:acetonitrile:formic acid=30:70:0.1    -   Flow rate; 1.0 mL/min    -   Detection; UV (220 nm)

Example 115 (The Enantiomer of Example 116)3-{(R)-4-[3-Chloro-4-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-5-isopropyl-4-methyl-2-oxo-3,4-dihydro-2H-pyrimidin-1-yl}-propionicacid

3-{(R)-4-[3-Chloro-4-(4,4-dimethyl-1l-cyclohex-1l-enyl)-phenyl]-5-isopropyl-4-methyl-2-oxo-3,4-dihydro-2H-pyrimidin-1-yl}-propionicacid ethyl ester obtained by Example 116 Step 12 was treated accordingto Example 116 Step 13 to give the titled compound (25 mg). Theretention time of the resulted enantiomer (R-enantiomer) was 6.0minutes.

The analytical condition in the chiral column is shown as follows.

-   -   Measuring instrument; HPLC system Shimadzu Corporation        high-performance liquid chromatograph prominence    -   Column; DAICEL CHIRALPAK AD-3R 0.46 cmφ×15 cm    -   Column temperature; 40° C.    -   Mobile phase; water:acetonitrile:formic acid=30:70:0.1    -   Flow rate; 1.0 mL/min    -   Detection; UV (220 nm)

Example 130 Preparation of4-{4-[3-chloro-4-(3,3-dimethyl-butyl)-phenyl]-4-methyl-2-oxo-1,2,3,4-tetrahydro-pyrimidin-5-yl}-4-methyl-pentanoicacid (an Optically Active Compound) Step 15-(tert-Butyl-dimethyl-silanyloxy)-2,2-dimethyl-pentanoic acid ethylester

Diisopropylamine (14.3 mL) and tetrahydrofuran (70 mL) were mixed underargon gas. To the reaction solution was added dropwise 1.55Mn-butyllithium/hexane solution (65.8 mL) at −78° C., and the reactionsolution was stirred for 10 minutes under ice cooling. To the reactionsolution was added dropwise a mixed solution of isobutanoic acid ethylester (13.6 mL) in tetrahydrofuran (70 mL) at −78° C., and the reactionsolution was stirred at −78° C. for 1.5 hours. To the reaction solutionwas added dropwise a mixed solution of3-bromopropoxy-tert-butyldimethylsilane (23.9 mL) in tetrahydrofuran (30mL) at −78° C., and the reaction solution was stirred at −78° C. for 5.5hours and then stirred at room temperature for 3 days. To the reactionsolution was added aqueous saturated ammonium chloride solution, whichwas then extracted with ethyl acetate. The organic layer was washed withaqueous saturated sodium chloride solution, and dried over sodiumsulfate. After removing sodium sulfate on a filter, the filtrate wasconcentrated under reduced pressure. The resulted residue was purifiedthrough silica gel column chromatography (ethyl acetate:hexane=1:20) togive the titled compound (26.4 g).

¹H-NMR (400 MHz, CDCl₃) 0.04 (s, 6H), 0.89 (s, 9H), 1.17 (s, 6H), 1.24(t, J=7.25 Hz, 3H), 1.41-1.50 (m, 2H), 1.56-1.51 (m, 2H), 3.58 (t,J=6.45 Hz, 2H), 4.11 (q, J=6.85 Hz, 2H)

Step 2 5-(tert-Butyl-dimethyl-silanyloxy)-2,2-dimethyl-pentan-1-ol

5-(tert-Butyl-dimethyl-silanyloxy)-2,2-dimethyl-pentanoic acid ethylester (26.5 g) was mixed in tetrahydrofuran (200 mL) under argon gas. Tothe reaction solution was added dropwise 1M diisobutylaluminumhydride/toluene solution (210 mL) at −78° C., and the reaction solutionwas stirred at −78° C. for 40 minutes. To the reaction solution wereadded ethyl acetate and 1M aqueous Rochelle salt solution (500 mL), andthe reaction solution was stirred at room temperature for 30 minutes.The reaction solution was extracted with ethyl acetate. The organiclayer was washed sequentially with 0-5M hydrochloric acid (2×200 mL),water (2×200 ML), saturated aqueous sodium hydrogen carbonate solution,and aqueous saturated sodium chloride solution, and dried over sodiumsulfate. After removing sodium sulfate on a filter, the filtrate wasconcentrated to give the titled compound (24.3 g).

¹H-NMR (400 MHz, CDCl₃) 0.06 (s, 6H), 0.87 (s, 6H), 0.90 (s, 9H),1.25-1.29 (m, 2H), 1.46-1.56 (m, 2H), 3.32 (s, 2H), 3.60 (t, J=6.45 Hz,2H)

Step 3 5-(tert-Butyl-dimethyl-silanyloxy)-2,2-dimethyl-pentanal

5-(tert-Butyl-dimethyl-silanyloxy)-2,2-dimethyl-pentan-1-ol (24.3 g) andtriethylamine (38.2 mL) were mixed in dichloromethane (100 mL). To thereaction solution was added dropwise a mixed solution of sulfur trioxidepyridine complex (20.1 g) in DMSO (130 mL) under ice cooling, and thereaction solution was stirred at room temperature for 2 hours. To thereaction solution was added saturated aqueous sodium hydrogen carbonatesolution (100 mL), which was then extracted with ethyl acetate. Theorganic layer was washed sequentially with 0.5M hydrochloric acid (3×200mL), water (150 mL), saturated aqueous sodium hydrogen carbonatesolution (100 mL), and aqueous saturated sodium chloride solution, anddried over sodium sulfate. After removing sodium sulfate on a filter,the filtrate was concentrated to give the titled compound (25.2 g).

¹H-NMR (400 MHz, CDCl₃) 0.04 (s, 6H), 0.89 (s, 9H), 1.05 (s, 6H),1.47-1.41 (m, 2H), 1.54-1.48 (m, 2H), 3.59 (t, J=6.45 Hz, 2H), 9.45 (s,1H)

Step 4 (E)-7-(tert-Butyl-dimethyl-silanyloxy)-4,4-dimethyl-hept-2-enoicacid ethyl ester

Sodium hydride (60 w/w %) (4.40 g) was mixed in tetrahydrofuran (100 mL)under argon gas. To the reaction solution was added dropwise ethyldiethylphosphonoacetate (21.8 mL) under ice cooling, and the reactionsolution was stirred at room temperature for 40 minutes. To the reactionsolution was added dropwise a mixed solution of5-(tert-butyl-dimethyl-silanyloxy)-2,2-dimethyl-pentanal (21.9 g) intetrahydrofuran (50 mL) under ice cooling, and the reaction solution wasstirred at room temperature for 75 minutes. To the reaction solution wasadded aqueous saturated ammonium chloride solution (150 mL) under icecooling, which was extracted with ethyl acetate. The organic layer waswashed sequentially with water (150 mL) and aqueous saturated sodiumchloride solution, and dried over sodium sulfate. After removing sodiumsulfate on a filter, the filtrate was concentrated.

The resulted residue was purified through silica gel columnchromatography (ethyl acetate:hexane=1:20) to give the titled compound(27.1 g).

¹H-NMR (400 MHz, CDCl₃) 0.04 (s, 6H), 0.89 (s, 9H), 1.05 (s, 6H), 1.29(t, J=7.05 Hz, 3H), 1.36-1.47 (m, 4H), 3.56 (t, J=6.04 Hz, 2H), 4.19 (q,J=7.25 Hz, 2H), 5.72 (d, J=16.12 Hz, 1H), 6.90 (d, J=16.12 Hz, 1H)

Step 5(E)-7-(tert-Butyl-dimethyl-silanyloxy)-4,4-dimethyl-hept-2-en-1-ol

(E)-7-(tert-Butyl-dimethyl-silanyloxy)-4,4-dimethyl-hept-2-enoic acidethyl ester (27.1 g) was mixed in tetrahydrofuran (200 mL) under argongas. To the reaction solution was added dropwise 1M diisobutylaluminumhydride/toluene solution (190 mL) at −78° C., and the reaction solutionwas stirred at −78° C. for 1.5 hours. To the reaction solution was added0.5M hydrochloric acid (200 mL), which was then extracted with ethylacetate (500 mL). The organic layer was washed sequentially with 0.5Mhydrochloric acid (2×150 mL), water (150 mL), saturated aqueous sodiumhydrogen carbonate solution (100 mL), and aqueous saturated sodiumchloride solution, and dried over sodium sulfate. After removing sodiumsulfate on a filter, the filtrate was concentrated to give the titledcompound (23.6 g).

¹H-NMR (400 MHz, CDCl₃) 0.04 (s, 6H), 0.89 (s, 9H), 0.99 (s, 6H), 1.22(brs, 1H), 1.31-1.27 (m, 2H), 1.40-1.48 (m, 2H), 3.56 (t, J=6.85 Hz,2H), 4.11 (d, J=5.24 Hz, 2H), 5.53 (dt, J=15.72, 5.64 Hz, 1H), 5.63 (dt,J=15.72, 0.81 Hz, 1H)

Step 6 2-[3-Chloro-4-(3,3-dimethyl-butyl)-phenyl]-propionic acid(E)-7-(tert-butyl-dimethyl-silanyloxy)-4,4-dimethyl-hept-2-enyl ester

2-[3-Chloro-4-(3,3-dimethylbutyl)phenyl]propionic acid (21.3 g),7-(tert-butyldimethylsilyloxy)-4,4-dimethyl-2-heptenol (21.6 g), and4-dimethylaminopyridine (11.6 g) were mixed in dichloromethane (250 mL).To the reaction solution was added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (18.2 g)under ice cooling, and the reaction solution was stirred at roomtemperature for 16 hours. The reaction solution was concentrated underreduced pressure, and to the residue was added water (150 mL), which wasthen extracted with ethyl acetate (500 mL). The organic layer was washedsequentially with water (150 mL) and aqueous saturated sodium chloridesolution, and dried over sodium sulfate. After removing sodium sulfateon a filter, the filtrate was concentrated. The resulted residue waspurified through silica gel column chromatography (ethylacetate:hexane=1:20) to give the titled compound (40.1 g).

¹H-NMR (400 MHz, CDCl₃) 0.04 (s, 6H), 0.89 (s, 9H), 0.95 (s, 6H), 0.97(s, 9H), 1.23-1.27 (m, 2H), 1.35-1.47 (m, 4H), 1.47 (d, J=7.25 Hz, 3H),2.63-2.67 (m, 2H), 3.55 (t, J=6.45 Hz, 2H), 3.66 (q, J=7-12 Hz, 1H),4.52 (dt, J=6.45, 1.21 Hz, 2H), 5.38 (dt, J=15.72, 6.45 Hz, 1H), 5.59(dt, J=15.72, 1.21 Hz, 1H), 7.11 (dd, J=7.66, 1.61 Hz, 1H), 7.15 (d,J=8.06 Hz, 1H), 7.28 (d, J=1.61 Hz, 1H)

Step 77-(tert-Butyl-dimethyl-silanyloxy)-2-[3-chloro-4-(3,3-dimethyl-butyl)-pheny1]-2,4,4-trimethyl-3-vinyl-heptanoicacid

Diisopropylamine (22.7 mL) was mixed in tetrahydrofuran (200 mL) underargon gas. To the reaction solution was added dropwise 1.55Mn-butyllithium/hexane solution (100 mL) at −78° C., and the reactionsolution was stirred under ice cooling for 20 minutes. To the reactionsolution was added dropwise a mixed solution of2-[3-chloro-4-(3,3-dimethyl-butyl)-phenyl]-propionic acid(E)-7-(tert-butyl-dimethyl-silanyloxy)-4,4-dimethyl-hept-2-enyl ester(40.1 g) in tetrahydrofuran (250 mL) at −78° C., and the reactionsolution was stirred under ice cooling for 1 hour. To the reactionsolution was added chlorotrimethylsilane (20.8 mL) at −78° C., and thereaction solution was stirred at −78° C. for 1.5 hours and then stirredat room temperature for 19.5 hours. To the reaction solution was added1M hydrochloric acid (312 mL) under ice cooling, which was thenextracted with ethyl acetate (500 mL). The organic layer was washedsequentially with 18 w/v % aqueous sodium chloride solution (300 mL) andaqueous saturated sodium chloride solution, and dried over sodiumsulfate. After removing sodium sulfate on a filter, the filtrate wasconcentrated. The resulted residue was purified through silica gelcolumn chromatography (ethyl acetate:hexane=l:4) to give the titledcompound (14.5 g).

¹H-NM.R (400 MHz, CDCl₃) 0.03 (s, 3.0H), 0.05 (s, 3.0H), 0.51 (s, 1.5H),0.78 (s, 1.5H), 0.89 (s, 4.5H), 0.90 (s, 4.5H), 0.93 (s, 1.5H), 0.95 (s,4.5H), 0.97 (s, 4.5H), 1.02 (s, 1.5H), 1.20-1.60 (m, 6.0H), 1.71 (s,1.5H), 1.72 (s, 1.5H), 2.59-2.67 (m, 2.0H), 3.07-3.11 (m, 1.0H), 3.45(t, J=6.85 Hz, 1.0H), 3.57 (t, J=7.25 Hz, 1.0H), 4.56 (dd, J=16.92, 2.01Hz, 0.5H), 4.74 (dd, J=10.28, 2.22 Hz, 0.5H), 5.13-5.17 (m, 1.0H),5.24-5.34 (m, 0.5H), 5.84-5.93 (m, 0.5H), 7.07 (d, J=8.06 Hz, 0.5H),7.13 (d, J=8.46 Hz, 0.5H), 7.28-7.24 (m, 0.5H), 7.39 (d, J=2.01 Hz,0.5H), 7.46 (dd, J=8.46, 2.01 Hz, 0.5H), 7.58 (d, J=2.01 Hz, 0.5H)

Step 8tert-Butyl-(5-{1-[3-chloro-4-(3,3-dimethyl-butyl)-phenyl]-1-isocyanatoethyl}-4,4-dimethyl-hept-6-enyloxy)-dimethyl-silane

7-(tert-Butyl-dimethyl-silanyloxy)-2-[3-chloro-4-(3,3-dimethyl-buty1)-phenyl[-2,4,4-trimethyl-3-vinyl-heptanoicacid (7.17 g) and triethylamine (2.86 mL) were mixed in toluene (100mL). To the reaction solution was added diphenyl phosphoryl azide (4.42mL), and the reaction solution was stirred at 110° C. for 3 hours. Thereaction solution was concentrated under reduced pressure, and theresulted residue was purified through silica gel column chromatography(ethyl acetate:hexane=1:60) to give the titled compound (5.12 g).

¹H-NMR (400 MHz, CDCl3) 0.02 (s, 3.0H), 0.04 (s, 3.0H), 0.53 (s, 1.5H),0.75 (s, 1.5H), 0.81 (s, 1.5H), 0.88 (s, 4.5H), 0.89 (s, 4.5H), 0.91 (s,1.5H), 0.98 (s, 4.5H), 0.98 (s, 4.5H), 1.12-1.48 (m, 6.0H), 1.60 (s,1.5H), 1.81 (s, 1.5H), 2.34-2.42 (m, 1.0H), 2.64-2.69 (m, 2.0H),3.36-3.41 (m, 1.0H), 3.49 (t, J=6.45 Hz, 1.0H), 4.77 (dd, J=17.13, 1.81Hz, 0.5H), 5.06-5.12 (m, 1.0H), 5.29 (dd, J=10.07, 2.01 Hz, 0.5H),5.74-5.83 (m, 0.5H), 5.88-5.98 (m, 0.5H), 7.28-7.13 (m, 2.0H), 7.33 (d,J=2.01 Hz, 0.5H), 7.37 (d, J=2.01 Hz, 0.5H)

Step 9{6-(tert-Butyl-dimethyl-silanyloxy)-1-[3-chloro-4-(3,3-dimethyl-butyl)-phenyl]-1,3,3-trimethy1-3-vinyl-hexyl}-urea

tert-Butyl-(5-{1-[3-chloro-4-(3,3-dimethyl-butyl)-phenyl]-1-isocyanatoethyl}-4,4-dimethyl-hept-6-enyloxy)-dimethyl-silane(552 mg) was mixed in tetrahydrofuran (10 mL). To the reaction solutionwas added 2M ammonia/methanol solution (3.18 mL), and the reactionsolution was stirred at room temperature for 18.5 hours. The reactionsolution was concentrated under reduced pressure, and the resultedresidue was purified through silica gel column chromatography (ethylacetate:hexane=2:1) to give the titled compound (574 mg).

¹H-NMR (400 MHz, CDCl₃) 0.02 (s, 3.0H), 0.03 (s, 3.0H), 0.51 (s, 1.5H),0.74 (s, 1.5H), 0.76 (s, 1.5H), 0.84 (s, 1.5H), 0.88 (s, 4.5H), 0.88 (s,4.5H), 0.97 (s, 4.5H), 0.98 (s, 4.5H), 1.13-1.48 (m, 6.0H), 1.84 (s,1.5H), 1.88 (s, 1.5H), 2.22 (d, J=10.48 Hz, 0.5H), 2.34 (d, J=10.88 Hz,0.5H), 2.63-2.69 (m, 2.0H), 3.35-3.41 (m, 1.0H), 3.46 (t, J=5.91 Hz,1.0H), 3.95 (s, 1.0H), 4.15 (s, 1.0H), 4.85 (dd, J=17.13, 1.81 Hz,0.5H), 5.09 (dd, J=10.07, 2.01 Hz, 0.5H), 5.23-5.31 (m, 1.0H), 5.39-5.43(m, 1.0H), 5.70-5.80 (m, 0.5H), 5.94-6.04 (m, 0.5H), 7.13-7.20 (m,1.5H), 7.36-7.32 (m, 1.0H), 7.49 (d, J=1.61 Hz, 0.5H)

Step 104-[3-Chloro-4-(3,3-dimethyl-butyl)-pheny1]-5-(4-hydroxy-1,1-dimethyl-butyl)-4-methyl-3,4-dihydro-1H-pyrimidin-2-one(Optically Active Compound)

{6-(tert-Butyl-dimethyl-silanyloxy)-1-[3-chloro-4-(3,3-dimethyl-butyl-phenyl]-1,3,3-trimethyl-3-vinyl-hexyl}-urea(574 mg) was mixed in methanol (10 mL). The reaction solution wasstirred at −78° C. for 1 hour under ozone flow. To the reaction solutionwere added dimethylsulfide (0.785 mL) at −78° C. and then 2Mhydrochloric acid/methanol solution (1.06 mL) under ice cooling. Thereaction solution was stirred overnight, which was then concentrated. Tothe resulted residue was added saturated aqueous sodium hydrogencarbonate solution, which was then extracted with ethyl acetate. Theorganic layer was washed sequentially with water and aqueous saturatedsodium chloride solution, and dried over sodium sulfate. After removingsodium sulfate on a filter, the filtrate was concentrated. The resultedresidue was purified through silica gel column chromatography(methanol:chloroform=l:10) to give a racemate of the titled compound(257 mg).

The racemate was separated and purified by a recycling preparativechromatograph.

The titled compound (103 mg) was obtained as a compound in a fractioneluted later in a recycling preparative chromatograph (separationcondition A2).

The compound was analyzed in the analytical condition B2, and theretention time was 5.6 minutes and the optical purity was >99% ee.

The enantiomer of the titled compound was obtained as a compound in afraction eluted earlier in a recycling preparative chromatograph(separation condition A2).

The compound was analyzed in the analytical condition B2, and theretention time was 3.8 minutes.

The separation condition is shown as follows.

(Separation Condition A2)

-   -   Separation instrument; Recycling preparative chromatograph        LC-9225 NEXT SERIES Japan Analytical Industry Co., Ltd.    -   Column; DAICEL CHIRALPAK IA 2.0 cmφ×25 cm    -   Mobile phase; hexane:2-propanol=80:20    -   Flow rate; 10.0 mL/min    -   Detection; UV (254 nm)

The analytical condition in the chiral column is shown as follows.

(Analytical Condition B2)

-   -   Measuring instrument HPLC system Shimadzu Corporation        high-performance liquid chromatograph prominence    -   Column; DAICEL CHIRALPAK IA-3 0.46 cmφ×15 cm    -   Column temperature; 40° C.    -   Mobile phase; hexane:2-propanol=80:20    -   Flow rate; 1.0 mL/min    -   Detection; UV (254 nm)

¹H-NMR (400 MHz, CDCl₃) 0.84 (s, 3H), 0.97 (s, 3H), 0.98 (s, 9H),1.24-1.48 (m, 6H), 1.84 (s, 3H), 2.65-2.69 (m, 2H), 3.55-3.45 (m, 2H),4.66 (s, 1H), 6.07 (d, J=5.24 Hz, 1H), 6.60 (s, 1H). 7.17 (d, J=8.06Hz, 1. H), 7.31 (dd, J=8.06, 2.01 Hz, 1H), 7.46 (d, J=2.01 Hz, 1H)

Step 114-{4-[3-Chloro-4-(3,3-dimethyl-butyl)-phenyl]-4-methyl-2-oxo-1,2,3,4-tetrahydro-pyrimidin-5-yl}-4-methyl-pentanal(Optically Active Compound)

4-[3-Chloro-4-(3,3-dimethyl-butyl)-phenyl]-5-(4-hydroxy-1,1-dimethyl-butyl)-4-methyl-3,4-dihydro-1H-pyrimidin-2-one(22.6 mg) obtained in the previous step was mixed in chloroform (2.0mL). To the reaction solution was added Dess-Martin Periodinane (67.7mg) under ice cooling, and the reaction solution was stirred under icecooling for 1 hour. To the reaction solution were added 10 w/v % aqueoussodium sulfite solution and saturated aqueous sodium hydrogen carbonatesolution, which was then extracted with ethyl acetate. The organic layerwas washed sequentially with saturated aqueous sodium hydrogen carbonatesolution and aqueous saturated sodium chloride solution, and dried oversodium sulfate. After removing sodium sulfate on a filter, the filtratewas concentrated to give the titled compound (25.1 mg).

¹H-NMR (400 MHz, CDCl3) 0.86 (s, 3H), 0.98 (s, 9H), 0.99 (s, 3H),1.27-1.19 (m, 1H), 1.42-1.47 (m, 2H), 1.49-1.56 (m, 1H), 1.84 (s, 3H),2.24-2.32 (m, 2H), 2.65-2.69 (m, 2H), 4.62 (s, 1H), 6.07 (d, J=5.24 Hz,1H), 6.43 (s, 1H), 7.17 (d, J=8.06 Hz, 1H), 7.30 (dd, J=8.06, 2.01 Hz,1H), 7.46 (d, J=2.01 Hz, 1H), 9.66 (t, J=1.21 Hz, 1H)

Step 124-{4[3-Chloro-4-(3,3-dimethyl-butyl)-phenyl]-4-methyl-2-oxo-1,2,3,4-tetrahydro-pyrimidin-5-y1}-4-methyl-pentanoicacid (Optically Active Compound)

4-{4-[3-Chloro-4-(3,3-dimethyl-butyl)-phenyl]-4-methyl-2-oxo-1,2,3,4-tetrahydro-pyrimidin}-5-yl-4-methyl-pentanal(25.1 mg) obtained in the previous step, 2-methyl-2-butene (0.0588 mL),and 1M aqueous sodium dihydrogenphosphate solution (0.555 mL) were mixedin tert-butanol (1.5 mL) and acetonitrile (3.0 mL). To the reactionsolution was added 0.166M aqueous sodium chlorite solution (0.500 mL),and the reaction solution was stirred at room temperature for 2.5 hours.To the reaction solution were added 10 w/v % aqueous sodium sulfitesolution and 1M hydrochloric acid, which was then extracted with ethylacetate. The organic layer was washed with aqueous saturated sodiumchloride solution, and dried over sodium sulfate. After removing sodiumsulfate on a filter, the filtrate was concentrated. The resulted residuewas purified through thin layer silica gel chromatography(methanol:chloroform=1:9) to give the titled compound (13.4 mg).

Example 154 Preparation of3-{(S)-4-[3-chloro-4-(3,3-dimethyl-butyl)-phenyl]-5-isopropyl-4-methyl-2-oxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-cyclobutanecarboxylicacid Step 1 4-Benzyloxy-butylaldehyde

4-Benzyloxy-butan-1-ol (5.0 g), potassium bromide (0.66 g), and2,2,6,6-tetramethylpiperidine 1-oxyl free radical (43.1 mg) were mixedin toluene (15 mL), ethyl acetate (15 mL), and water (3 mL). To thereaction solution were added dropwise a mixed solution of potassiumhydrogen carbonate (5.55 g) in water (15 mL) and then 15 w/w % aqueoussodium hypochlorite solution (16.5 mL) under ice cooling. The reactionsolution was stirred under ice cooling for 1.5 hours. To the reactionsolution was added 15 w/w % aqueous sodium hypochlorite solution (4 mL),and the reaction solution was stirred for additional 2 hours. Thereaction solution was extracted with toluene. The organic layer waswashed sequentially with water, a mixed solution of potassium iodide (73mg) in 1M hydrochloric acid (5 mL), a mixed solution of sodiumthiosulfate (2.3 g) and potassium carbonate (4.02 g) in water (8.3 mL),and aqueous saturated sodium chloride solution, and dried over magnesiumsulfate. After removing magnesium sulfate on a filter, the filtrate wasconcentrated under reduced pressure to give the titled compound (4.08 g)as a crude product.

¹H-NMR (400 MHz, CDCl₃) 1.91-1.99 (m, 2H), 2.55 (td, J=7.05, 1.62 Hz,2H), 3.51 (t, J=6.13 Hz, 2H), 4.49 (s, 2H), 7.15-7.37 (m, 5H), 9.79 (t,J=1.62 Hz, 1H)

Step 2 1((E)-4-Benzyloxy-but-1-enyl)-piperidine

4-Benzyloxy-butylaldehyde (4.08 g) and Molecular Sieves 4A (15.8 g) weremixed in toluene (55 mL). To the reaction solution was added a mixedsolution of piperidine (1.36 mL) in toluene (15 mL) under ice cooling,and the reaction solution was stirred at room temperature overnight.After removing an insoluble on a filter, the filtrate was concentratedunder reduced pressure to give the titled compound (5.24 g) as a crudeproduct.

¹H-NMR (400 MHz, DMSO-D₆) 1.38-1.65 (m, 6H), 2.13-2.20 (m, 2H), 2.69 (t,J=5.09 Hz, 4H), 3.35 (t, J=7.05 Hz, 2H), 4.17-4.25 (m, 1H), 4.44 (s,2H), 5.86 (d, J=13.87 Hz, 1H), 7.14-7.36 (m, 5H)

Step 3 3-(2-Benzyloxy-ethyl)-2-piperidin-1-yl-cyclobutanecarboxylic acidethyl ester

1((E)-4-Benzyloxy-but-1-enyl)-piperidine (5.24 g) and hydroquinone (13.2mg) were mixed in acetonitrile (3.45 mL). To the reaction solution wasadded ethyl acrylate (1.89 mL), and the reaction solution was stirred at85° C. overnight. The reaction solution was concentrated under reducedpressure to give the titled compound (6.45 g) as a crude product.

¹H-NMR (400 MHz, DMSO-D₆) 1.15 (t, J=7.05 Hz, 3H), 1.30-2.35 (m, 16H),2.65-2.79 (m, 1H), 3.36-3.45 (m, 3H), 4.00-4.08 (m, 2H), 4.42 (s, 2H),7.16-7.36 (m, 5H)

Step 4 3-(2-Benzyloxy-ethyl)-cyclobut-1-enecarboxylic acid

3-(2-Benzyloxy-ethyl)-2-piperidin-1-yl-cyclobutariecarboxylic acid ethylester (6.45 g) was mixed in methyl p-toluenesulfonate (1.92 mL). Thereaction solution was stirred at 105° C. for 1 hour. The reactionsolution was cooled to 50° C., and water (13.5 mL) was added thereto. Tothe reaction solution was added potassium hydroxide (3.04 g, 85%) underice cooling, and then the reaction solution was stirred at 45° C.overnight. The reaction solution was washed sequentially withdiethylether and a mixed solution of diethylether-hexane solution (1:1).Concentrated hydrochloric acid was added to the aqueous layer under icecooling so that the aqueous layer was adjusted to pH 1, which was thenextracted with ethyl acetate. The organic layer was washed sequentiallywith water and aqueous saturated sodium chloride solution, and driedover magnesium sulfate. After removing magnesium sulfate on a filter,the filtrate was concentrated under reduced pressure to give the titledcompound (4.57 g) as a crude product.

¹H-NMR (400 MHz, CDCl₃) 1.82-1.88 (m, 8H), 2.50 (t, J=7.17 Hz, 1H),2.84-2.93 (m, 2H), 3.51-3.56 (m, 2H), 4.51 (s, 3H), 6-98 (d, J=0.92 Hz,1H), 7.26-7.38 (m, 5H)

Step 5 trans-3-(2-Benzyloxy-ethyl)-cyclobutanecarboxylic acid

3-(2-Benzyloxy-ethyl)-cyclobut-1-enecarboxylic acid (4.57 g) and zinc(4.17 g) were mixed in tetrahydrofuran (53 mL) and water (21.2 mL). Tothe reaction solution was added dropwise concentrated hydrochloric acid(31.8 mL) under ice cooling, and the reaction solution was stirred atroom temperature for 2.5 hours. Tetrahydrofuran was distilled away underreduced pressure, which was then extracted with ethyl acetate. Theorganic layer was washed sequentially with water and aqueous saturatedsodium chloride solution, and dried over magnesium sulfate. Afterremoving magnesium sulfate on a filter, the filtrate was concentratedunder reduced pressure. The resulted residue was purified through silicagel column chromatography (acetone:hexane=1:9->1:6) to give the titledcompound (2.93 g).

¹H-NMR (400 MHz, CDCl₃) 1.78 (q, J=6.73 Hz, 2H), 1.92-2.01 (m, 3H),2.38-2.59 (m, 5H), 3.09-3.17 (m, 1H), 3.43 (t, J=6.73 Hz, 2H), 4.48 (s,2H), 7.26-7.36 (m, 5H)

Step 6 trans-3-(2-Benzyloxy-ethyl)-cyclobutanecarboxylic acid ethylester

trans-3-(2-Benzyloxy-ethyl)-cyclobutanecarboxylic acid (2.93 g),4-dimethylaminopyridine (0.15 g), 1-hydroxybenzotriazole monohydrate,and ethanol (0.86 mL) were mixed in chloroform. To the reaction solutionwas added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride(2.84 g) under ice cooling, and the reaction solution was stirred atroom temperature overnight. The reaction solution was concentrated underreduced pressure and water was added to the resulted residue, which wasextracted with ethyl acetate. The organic layer was washed sequentiallywith water and aqueous saturated sodium chloride solution, and driedover magnesium sulfate. After removing magnesium sulfate on a filter,the filtrate was concentrated under reduced pressure. The resultedresidue was purified through silica gel column chromatography (ethylacetate:hexane=1:16) to give the titled compound (2.37 g).

¹H-NMR (400 MHz, CDCl₃) 1.26 (t, J=7.13 Hz, 4H), 1.78 (q, J=6.82 Hz,2H), 1.89-1.96 (m, 2H), 2.35-2.44 (m, 2H), 2.47-2.54 (m, 1H), 3.03-3.11(m, 1H), 3.42 (t, J=6.82 Hz, 2H), 4.14 (q, J=7.13 Hz, 3H), 4.48 (s, 2H),7.24-7.36 (m, 11H)

Step 7 trans-3-(2-Hydroxy-ethyl)-cyclobutanecarboxylic acid ethyl ester

trans-3-(2-Benzyloxy-ethyl)-cyclobutanecarboxylic acid ethyl ester (2.37g) was mixed in tetrahydrofuran (24 mL). To the reaction solution wasadded 10 w/w % palladium hydroxide/activated carbon (0.24 g), and thereaction solution was stirred at room temperature for 3.5 hours at anordinary pressure under hydrogen gas. After removing palladiumhydroxide/activated carbon on a filter, the filtrate was concentratedunder reduced pressure. The resulted residue was purified through silicagel column chromatography (ethyl acetate:hexane=1:4->1:3->1:1.5) to givethe titled compound (1.24 g).

¹H-NMR (400 MHz, CDCl₃) 1.19 (brs, 1H), 1.26 (t, J=7.17 Hz, 3H), 1.74(q, J=6.94 Hz, 2H), 1.87-1.97 (m, 2H), 2.37-2.45 (m, 2H), 2.46-2.55 (m,1H), 3.04-3.13 (m, 1H), 3.57-3.64 (m, 2H), 4.14 (q, J=7.17 Hz, 3H)

Step 8 trans-3-Carboxymethyl-cyclobutanecarboxylic acid ethyl ester

trans-3-(2-Hydroxy-ethyl)-cyclobutanecarboxylic acid ethyl ester (1.24g) and 2,2,6,6-tetramethylpiperidine-1-oxyl free radical (39 mg) weremixed in acetonitrile (12 mL) and 1M phosphate buffer (5.5 mL). To thereaction solution were added sodium chlorite (0.91 g) and 15 w/w %aqueous sodium hypochlorite solution (74 L) under ice cooling, and thereaction solution was stirred under ice cooling for 5 minutes and thenstirred at room temperature for 4 hours. To the reaction solution wasadded aqueous sodium sulfite solution under ice cooling, and thereaction solution was stirred at room temperature for 30 minutes. Anaqueous potassium hydrogensulfate solution was added to the reactionsolution so that the aqueous layer was adjusted to pH 2, which was thenextracted with ethyl acetate. The organic layer was washed with aqueoussaturated sodium chloride solution, and dried over magnesium sulfate.After removing magnesium sulfate on a filter, the filtrate wasconcentrated under reduced pressure. The resulted residue was purifiedthrough silica gel column chromatography (methanol:chloroform=1:20) togive the titled compound (1.18 g).

¹H-NMR (400 MHz, CDCl₃) 1.26 (t, J=7.17 Hz, 4H), 1.98-2.05 (m, 2H),2.46-2.53 (m, 2H), 2.61-2.65 (m, 1H), 2.67-2.71 (m, 1H), 2.75-2.87 (m,1H), 3.06-3.14 (m, 1H), 4.15 (q, J=7.17 Hz, 2H)

Step 9 trans-3-(Benzyloxycarbonylaminomethyl)-cyclobutanecarboxylic acidethyl ester

trans-3-Carboxymethyl-cyclobutanecarboxylic acid ethyl ester (1.18 g),benzylalcohol (1.05 mL), and triethylamine (3.8 mL) were mixed intoluene (12 mL). To the reaction solution was added diphenyl phosphorylazide (1.6 mL) under ice cooling, and the reaction solution was stirredat room temperature for 15 minutes, then at 100° C. for 1 hour, and thenat 70° C. for 7 hours. To the reaction solution was added water at roomtemperature, which was then extracted with ethyl acetate. The organiclayer was washed sequentially with water, aqueous potassiumhydrogensulfate solution, aqueous sodium hydrogen carbonate solution,and aqueous saturated sodium chloride solution, and dried over sodiumsulfate. After removing sodium sulfate on a filter, the filtrate wasconcentrated under reduced pressure. The resulted residue was purifiedthrough silica gel column chromatography (ethylacetate:hexane=1:9->1:4->1:3) to give the titled compound (0.85 g).

¹H-NMR (400 MHz, CDCl₃) 1.25 (t, J=7.17 Hz, 3H), 1.93-2.00 (m, 2H),2.33-2.40 (m, 2H), 2.50-2.55 (m, 1H), 3.06-3.13 (m, 1H), 3.27-3.31 (m,2H), 4.14 (q, J=7.17 Hz, 3H), 4.72 (brs, 1H), 5.10 (s, 2H), 7.30-7.38(m, 5H)

Step 10 trans-3-Aminomethyl-cyclobutanecarboxylic acid ethyl ester

trans-3-(Benzyloxycarbonylaminomethyl)-cyclobutanecarboxylic acid ethylester (400 mg) was mixed in ethanol. To the reaction solution was added10 w/w % palladium/activated carbon (60 mg), and the reaction solutionwas stirred at room temperature overnight at an ordinary pressure underhydrogen gas overnight. After removing palladium/activated carbon on afilter, the filtrate was concentrated under reduced pressure to give thetitled compound (232 mg) as a crude product.

¹H-NMR (400 MHz, CDCl₃) 1.26 (t, J=7.17 Hz, 3H), 1.92-1.98 (m, 2H),2.34-2.43 (m, 3H), 2.76-2.79 (m, 2H), 3.04-3.12 (m, 1H), 4.15 (q, J=7.17Hz, 3H)

Step 11 trans-3-Isocyanatomethyl-cyclobutanecarboxylic acid ethyl ester

3-Aminomethyl-cyclobutanecarboxylic acid ethyl ester (232 mg) was mixedin dichloromethane (5.5 mL) and saturated aqueous sodium hydrogencarbonate solution (5.5 mL). To the reaction solution was addedtriphosgene (134 mg) under ice cooling, and the reaction solution wasstirred under ice cooling for 3 hours. The reaction solution wasextracted with chloroform. The organic layer was washed with aqueoussaturated sodium chloride solution, and dried over sodium sulfate. Afterremoving sodium sulfate on a filter, the filtrate was concentrated underreduced pressure to give the titled compound (236 mg) as a crudeproduct.

¹H-NMR (400 MHz, CDCl₃) 1.27 (t, J=7.11 Hz, 3H), 2.01-2.08 (m, 2H),2.37-2.45 (m, 2H), 2.58-2.68 (m, 1H), 3.04-3.13 (m, 1H), 3.36 (d, J=6.70Hz, 2H), 4.16 (q, 0.1=7.11 Hz, 2H)

Step 123-(3-{(R)-1-[3-Chloro-4-(3,3-dimethyl-butyl)-pheny1]-2-hydroxymethyl-1,3-dimethyl-buty1}-ureidomethyl)-cyclobutanecarboxylicacid ethyl ester

(R)-3-amino-3-[3-chloro-4-(3,3-dimethyl-butyl)-phenyl]-2-isopropyl-butan-1-ol(130 mg) obtained according to Example 87 (a method for preparationusing an optically active sulfinamide) Steps 1 to 8 was mixed intetrahydrofuran (0.5 mL). To the reaction solution was added a mixedsolution of trans-3-isocyanatomethyl-cyclobutanecarboxylic acid ethylester (56 mg) in tetrahydrofuran (0.5 mL) under ice cooling, and thereaction solution was stirred at room temperature overnight. To thereaction solution was added N,N,N′-trimethylethylenediamine (10 μ1),which was then concentrated under reduced pressure. The resulted residuewas purified through silica gel column chromatography(acetone:chloroform=l:6) to give the titled compound (128 mg,d.r.=79:21).

¹H-NMR (400 MHz, CDCl₃) 0.22 (d, J=6.94 Hz, 0.69H), 0.75 (d, J=6.94 Hz,2.31H), 0.80 (d, J=6.94 Hz, 2.31H), 0.95 (d, J=6.94 Hz, 0.69H), 0.97 (s,2.07H), 0.98 (s, 6.93H), 1.25 (t, J=7.17 Hz, 3H), 1.40-1.49 (m, 2.77H),1.64-1.87 (m, 6.23H), 2.14-2.40 (m, 3H), 2.63-2.69 (m, 2H), 2.94-3.19(m, 3H), 3.71-4.03 (m, 3H), 4.09-4.15 (m, 2H), 7.15-7.21 (m, 1H),7.24-7.30 (m, 1H), 7.35-7.43 (m, 2H)

Step 133-{(S)-4-[3-Chloro-4-(3,3-dimethyl-butyl)-phenyl]-5-isopropyl-4-methyl-2-oxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-cyclobutanecarboxylicacid ethyl ester

3-(3-{(R)-1-[3-Chloro-4-(3,3-dimethyl-butyl)-phenyl]-2-hydroxymethyl-1,3-dimethyl-butyl}-ureidomethyl)-cyclobutanecarboxylicacid ethyl ester (128 mg) and iodobenzene diacetate (90 mg) were mixedin dichloromethane (1.3 mL). To the reaction solution was added2,2,6,6-tetramethylpiperidine-1-oxyl free radical (2 mg) under icecooling, and the reaction solution was stirred at room temperature for 2hours. To the reaction solution was added trifluoroacetic acid (0.74μl), and the reaction solution was stirred for 1 hour. To the reactionsolution was added dropwise aqueous sodium sulfite solution under icecooling, and then thereto was added dropwise aqueous sodium hydrogencarbonate solution so that the aqueous layer was adjusted to pH 6. Theresulted mixed solution was extracted with ethyl acetate. The organiclayer was washed sequentially with water and aqueous saturated sodiumchloride solution, and dried over sodium sulfate. After removing sodiumsulfate on a filter, the filtrate was concentrated under reducedpressure. The resulted residue was purified through silica gel columnchromatography (ethyl acetate:hexane=1:3), followed by purification byrecycling preparative chromatograph to give the titled compound (72 mg).

The separation condition is shown as follows.

-   -   Separation instrument; Recycling preparative chromatograph        LC-9225 NEXT SERIES Japan Analytical Industry Co., Ltd.    -   Column; DAICEL CHIRALPAK IA-3 2.0 cmφ×25 cm    -   Mobile phase; hexane:2-propanol=90:10    -   Flow rate; 10.0 mL/min    -   Detection; UV (220 nm)

¹H-NMR (400 MHz, CDCl₃) 0.72 (d, J=6.82 Hz, 3H), 0.98 (s, 9H), 1.05 (d,J=6-82 Hz, 3H), 1.26 (t, J=7.13 Hz, 3H), 1.42-1.47 (m, 2H), 1.68 (s,3H), 1.86-1.94 (m, 1H), 2.04-2.11 (m, 2H), 2.35-2.42 (m, 2H), 2.63-2.77(m, 3H), 3.09-3.18 (m, 1H), 3.58 (d, J=7.63 Hz, 2H), 4.15 (q, J=7.09 Hz,2H), 4.62 (brs, 1H), 5.81 (s, 1H), 7.16 (d, J=8.04 Hz, 1H), 7.23 (dd,J=8.04, 1.91 Hz, 1H), 7.37 (d, J=1.81 Hz, 1H)

Step 143-{(S)-4-[3-Chloro-4-(3,3-dimethyl-butyl)-phenyl]-5-isopropyl-4-methyl-2-oxo-3,4-dihydro-2H-pyrindin-1-ylmethyl}-cyclobutanecarboxylicacid

3{(S)-4-[3-Chloro-4-(3,3-dimethyl-butyl)-phenyl]-5-isopropyl-4-methyl-2-oxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-cyclobutanecarboxylicacid ethyl ester (72 mg) was mixed in tetrahydrofuran (360 μl) andmethanol (360 μl). To the reaction solution was added dropwise 2Maqueous sodium hydroxide solution (296 l) under ice cooling, and thereaction solution was stirred at room temperature overnight. Thereaction solution was concentrated under reduced pressure, and theretowas added water. To the mixed solution was added 1M hydrochloric acid(590 μl) under ice cooling, and then the mixed solution was stirred atroom temperature. The precipitated solid was filtered to give the titledcompound (59 mg).

The specific optical rotation of the resulted compound was [α]_(D)²⁵=+141.20 (c=0.05, methanol).

The resulted compound was analyzed by a chiral column, and the retentiontime of the resulted titled compound was 10.1 minutes.

The analytical condition in the chiral column is shown as follows.

-   -   Measuring instrument; HPLC system Shimadzu Corporation        high-performance liquid chromatograph prominence    -   Column; DAICEL CHIRALPAK AD-3R 0.46 cmφ)×15 cm    -   Column temperature; 40° C.    -   Mobile phase; water:acetonitrile:formic acid=30:70:0.1    -   Flow rate; 1.0 mL/min    -   Detection; UV (220 nm)

Example 159 Preparation of4-{(S)-4-[3-chloro-4-(3,3-dimethyl-butyl)-pheny1]-5-isopropyl-4-methyl-2-oxo-3,4-dihydro-2H-pyrimidin-1-y1}-benzoicacid Step 1 (S)-2-Methyl-propane-2-sulfinic acid{(R)-1-[3-chloro-4-(3,3-dimethyl-butyl)-phenyl]-2-hydroxymethyl-1,3-dimethyl-butyl}amide

(R)-3-[3-Chloro-4-(3,3-dimethyl-butyl)-phenyl]-2-isopropyl-3-((S)-2-methyl-propane-sulfinylamino)-butyricacid methyl ester (3.39 g) prepared according to Example 87 (a methodfor preparation using an optically active sulfinamide) Steps 1 to 6 wasmixed in tetrahydrofuran (30 mL). To the reaction solution was addeddropwise 1M isobutylaluminum hydride/toluene solution (22.4 mL) at −78°C., and the reaction solution was stirred under ice cooling for 2.5hours. To the reaction solution was added saturated aqueous Rochellesalt solution, which was then extracted with ethyl acetate. The organiclayer was washed sequentially with aqueous saturated sodium chloridesolution and water, and then concentrated under reduced pressure. Theresulted residue was purified through silica gel column chromatography(ethyl acetate:hexane-1:2) to give the titled compound (3.01 g).

Step 2(R)-3-Amino-3-[3-chloro-4-(3,3-dimethyl-butyl)-phenyl]-2-isopropyl-butan-1-ol

(S)-2-Methyl-propane-2-sulfinic acid{(R)-1-[3-chloro-4-(3,3-dimethyl-butyl)-phenyl]-2-hydroxyrnetlayl-1,3-dimethyl-butyl}amide(3.0 g) was mixed in methanol (15 mL). To the reaction solution wasadded 2M hydrogen chloride/methanol solution (11.2 mL) under icecooling, and the reaction solution was left to stand at room temperatureovernight. The reaction solution was concentrated under reducedpressure, and to the residue was added saturated sodium carbonatesolution under ice cooling so that the aqueous layer was adjusted to bealkaline. The mixed solution was extracted with chloroform, and theorganic layer was dried over sodium sulfate. After removing sodiumsulfate on a filter, the filtrate was concentrated under reducedpressure to give the titled compound (2.37 g) as a crude product.

Step 34-(3-{(R)-1-[3-Chloro-4-(3.3-dimethyl-butyl)-pheny1]-2-hydroxymethyl-1,3-dimethyl-butyl}-ureido)-benzoicacid ethyl ester

(R)-3-Amino-3-[3-chloro-4-(3,3-dimethyl-butyl)-phenyl]-2-isopropyl-butan-1-ol(100 mg) was mixed in tetrahydrofuran (1.5 mL). To the reaction solutionwas added 4-isocyanatebenzoic acid ethyl ester (59 mg) under icecooling, and the reaction solution was stirred at room temperature for 1hour. To the reaction solution was added 4-isocyanatebenzoic acid ethylester (34 mg), and the reaction solution was concentrated under reducedpressure. The resulted residue was purified through silica gel columnchromatography (methanol:chloroform=5:95) to give the titled compound(139 mg).

¹H-NMR (400 MHz, CDCl₃) 0.74-0.83 (m, 3H), 0.83-0.88 (m, 3H), 0.92-1.01(m, 9H), 1.30-1.49 (m, 5H), 1.85-2.03 (m, 5H), 2.54-2.67 (m, 1H),3.76-4.02 (m, 1H), 4.28-4.40 (m, 2H), 6.24-6.42 (m, 1H), 7.10-7.56 (m,5H), 7.85-8.03 (m, 2H)

Step 44-{(S)-4-[3-Chloro-4-(3,3-dimethyl-butyl)-phenyl]-5-isopropyl-4-methyl-2-oxo-3,4-dihydro-2H-pyrimidin-1-yl}-benzoicacid ethyl ester

4-(3-{(R)-1-[3-Chloro-4-(3.3-dimethyl-butyl)-phenyl]-2-hydroxymethyl-1,3-dimethyl-butyl}-ureido)-benzoicacid ethyl ester (139 mg) and iodobenzene diacetate (182 mg) were mixedin dichloromethane (3.0 mL). To the reaction solution was added2,2,6,6-tetramethylpiperidine 1-oxyl (4.0 mg) under ice cooling, and thereaction solution was stirred at room temperature for 3 hours. To thereaction solution was added saturated aqueous sodium sulfite solutionunder ice cooling, which was then extracted with chloroform. The organiclayer was dried over sodium sulfate. After removing sodium sulfate on afilter, the filtrate was concentrated under reduced pressure. Theresulted residue was purified through silica gel column chromatography(ethyl acetate:hexane=3:1) to give the titled compound (33 mg).

¹H-NMR (400 MHz, CDCl3) 0.70-0.78 (m, 3H), 0.97 (s, 9H), 1.06-1.12 (m,3H), 1.34-1.41 (m, 3H), 1.42-1.49 (m, 2H), 1.79 (s, 3H), 1.92-2.03 (m,1H), 2.63-2.71 (m, 2H), 4.30-4.42 (m, 2H), 5.07 (brs, 1H), 6.18 (s, 1H),7.13-7.23 (m, 1H), 7.27-7.34 (m, 1H), 7.38-7.49 (m, 3H), 8.00-8.11 (m,2H)

Step 54-{(S)-4-[3-Chloro-4-(3,3-dimethyl-butyl)-phenyl]-5-isopropy1-4-methy1-2-oxo-3,4-dihydro-2H-pyrimidin-1-yl}-benzoicacid

4-{(S)-4-[3-Chloro-4-(3,3-dimethyl-butyl)-phenyl]-5-isopropyl-4-methyl-2-oxo-3,4-dihydro-2H-pyrimidin-1-yl}-benzoicacid ethyl ester (33 mg) was mixed in ethanol (1.0 mL) andtetrahydrofuran (1.0 mL). To the reaction solution was added 2M aqueoussodium hydroxide solution (0.132 mL), and the reaction solution wasstirred at room temperature for 90 minutes, and then stirred at 70° C.so that the reaction solution became cloudy. The reaction solution wasconcentrated under reduced pressure, and then thereto was added 2Maqueous hydrochloric acid solution (0.132 mL). The precipitated solidwas filtered to give the titled compound (21 mg).

The specific optical rotation of the resulted compound was [α]_(D)²⁵=+87.50 (c=0.25, methanol).

The resulted compound was analyzed by a chiral column, and the retentiontime of the resulted titled compound was 16.2 minutes.

The analytical condition in a chiral column is shown as follows.

-   -   Measuring instrument; HPLC system Shimadzu Corporation        high-performance liquid chromatograph prominence    -   Column; DAICEL CHIRALPAK AD-3R 0.46 cmφ×15 cm    -   Column temperature; 40° C.    -   Mobile phase; water:acetonitrile:formic acid=30:70:0.1    -   Flow rate; 1.0 mL/min    -   Detection; UV (220 nm)

Example 226 Step 14-(3-{(R)-1-[3-Chloro-4-(3.3-dimethyl-butyl)-phenyl]-2-hydroxymethyl-1,3-dimethyl-butyl}-ureido)-2-methoxy-benzoicacid methyl ester

(R)-3-Amino-3-[3-chloro-4-(3,3-dimethyl-butyl)-phenyl]-2-isopropyl-butan-1-ol(181 mg, corresponding to 0.5 mmol) prepared according to Example 159 (amethod for preparation using an optically active sulfinamide) Steps 1 to2 was mixed in tetrahydrofuran (5.0 mL), and thereto was added4-isocyanate-2-methoxy-benzoic acid methyl ester (114 mg) under icecooling. A cooling bath was removed, and the reaction solution wasstirred at room temperature overnight. The resulted solution was thenconcentrated under reduced pressure. The resulted residue was purifiedthrough silica gel column chromatography (ethyl acetate:hexane=4:1) togive the titled compound (139 mg).

Step 24-{(S)-4-[3-Chloro-4-(3,3-dimethyl-butyl)-phenyl]-5-isopropyl-4-methyl-2-oxo-3,4-dihydro-2H-pyrimidin-1-yl}-2-methoxy-benzoicacid methyl ester

4-(3-{(R)-1-[3-Chloro-4-(3.3-dimethyl-butyl)-phenyl]-2-hydroxymethyl-1,3-dimethyl-butyl}-ureido)-2-methoxy-benzoicacid methyl ester (139 mg) and dichloromethane (2.0 mL) were mixed, andthereto were added 2,2,6,6-tetramethylpiperidine 1-oxyl (4.0 mg) andiodobenzene diacetate (92 mg) under ice cooling. A cooling bath wasremoved, and the reaction solution was stirred for about 3 hours. Thentrifluoroacetic acid (119 mg) was added to the reaction solution. Thereaction solution was stirred at room temperature for 80 minutes, andthen thereto were added saturated aqueous sodium sulfite solution andchloroform, which was separated. The organic layer was dried over sodiumsulfate. After filtered through sodium sulfate, the filtrate wasconcentrated under reduced pressure. The resulted residue was purifiedthrough silica gel column chromatography (ethyl acetate:hexane=2:3),followed by purification by thin layer silica gel chromatography (ethylacetate:hexane=1:1) to give the titled compound (81 mg).

Step 34-{(S)-4-[3-Chloro-4-(3,3-dimethyl-butyl)-phenyl]-5-isopropyl-4-methyl-2-oxo-3,4-dihydro-2H-pyrimidin-1-yl}-2-methoxy-benzoicacid

4-{(S)-4-[13-Chloro-4-(3,3-dimethyl-buty1)-phenyl]-5-isopropyl-4-methyl-2-oxo-3,4-dihydro-2H-pyrimidin-1-yl}-2-methoxy-benzoicacid methyl ester (68 mg), methanol (2.0 mL), arid tetrahydrofuran (1.0mL) were mixed. To the reaction solution was added 2M aqueous sodiumhydroxide solution (0.2 mL) at room temperature, which was stirred at70° C. for about 3 hours. The reaction solution was concentrated underreduced pressure, and then thereto was added 2Maqueous hydrochloric acidsolution (0.2 mL). The precipitated solid was filtered and dried at 60°C. to give the titled compound (58 mg).

Example 229 Step 1 cis-(3-Hydroxymethyl-cyclobutyl)-acetic acidtert-butyl ester

cis-3-tert-Butoxycarbonylmethyl-cyclobutanoic acid (10.0 g) was mixedwith tetrahydrofuran (100 mL), and thereto was added dropwise 0.85Mborane-tetrahydrofuran/tetrahydrofuran solution (82 mL) at −16° C. Thereaction solution was stirred for 23 hours with naturally warming toroom temperature, and then thereto was added 6M hydrochloric acid (20mL). The reaction solution was concentrated, and then thereto were addedethyl acetate and water, which was separated. The organic layer waswashed sequentially with water (3 times) and aqueous saturated sodiumchloride solution, and dried over magnesium sulfate. After removingmagnesium sulfate on a filter, the filtrate was concentrated underreduced pressure to give the titled compound (8.93 g).

¹H-NMR (400 MHz, CDCl₃) 1.43 (s, 9H), 1.45-1.51 (m, 2H), 2.18-2.25 (m,2H), 2.29 (d, J=7.25 Hz, 2H), 2.36-2.43 (m, 1H), 2.58-2.48 (m, 1H), 3.55(d, J=6.45 Hz, 2H)

Step 2 cis-(3-Hydroxymethyl-cyclobutyl)-acetic acid methyl ester

cis-(3-Hydroxymethyl-cyclobutyl)-acetic acid tert-butyl ester (1.25 g)was mixed with chloroform (6.0 mL), and then thereto was addedtrifluoroacetic acid (3.0 mL) at room temperature. The mixture wasstirred for 71 hours, and then thereto was added trifluoroacetic acid(3.0 mL). The mixture was stirred at 60° C. for 1.5 hours, and thenconcentrated. After azeotropy with toluene (twice), the residue wasmixed with methanol (9.0 mL), and thereto was added 2Mtrimethylsilyldiazomethane n-hexane solution (9.4 mL). The reactionsolution was stirred for 1 hour at room temperature, and then theretowas added acetic acid (80 mL), which was concentrated. The resultedresidue was purified through silica gel column chromatography (ethylacetate:hexane=l:20->1:10->1:5->1:2->1:1)) to give the titled compound(983 mg). ¹H-NMR (400 MHz, CDCl₃) 1.43-1.52 (m, 2H), 2.18-2.27 (m, 2H),2.34-2.46 (m, 3H), 2.52-2.62 (m, 1H), 3.55 (d, J=6.28 Hz, 2H), 3.65 (s,3H)

Step 3 cis-(3-Methoxymethoxymethyl-cyclobutyl)-acetic acid methyl ester

cis-(3-Hydroxymethyl-cyclobutyl)-acetic acid methyl ester (500 mg) wasmixed with chloroform (5.0 mL), and thereto were added chloromethylmethyl ether (0.323 mL) and diisopropylethylamine (0.739 mL) under icecooling. The reaction solution was stirred for 20 hours at roomtemperature, and then thereto were added ethyl acetate and 0.5Mhydrochloric acid, which was separated. The organic layer was washedsequentially with 0.5N hydrochloric acid, water, aqueous sodium hydrogencarbonate solution, and aqueous saturated sodium chloride solution, anddried over sodium sulfate. After removing sodium sulfate on a filter,the filtrate was concentrated under reduced pressure. The resultedresidue was purified through silica gel column chromatography (ethylacetate:hexane=1:15->1:10) to give the titled compound (364 mg).

¹H-NMR (400 MHz, CDCl₃) 1.44-1.53 (m, 2H), 2.22-2.29 (m, 2H), 2.39 (d,J=7.25 Hz, 2H), 2.43-2.49 (m, 1H), 2.52-2.62 (m, 1H), 3.35 (s, 3H), 3.44(d, J=6.45 Hz, 2H), 3.65 (s, 3H), 4.60 (s, 2H)

Step 4(R)-3-[3-Chloro-4-(3,3-dimethyl-butyl)-phenyl]-2-(3-methoxymethoxymethyl-cyclobutyl)-3-((S)-2-methyl-propane-2-sulfinylamino)-butanoicacid methyl ester

Diisopropylamine (0.280 mL) was mixed in tetrahydrofuran (1.0 mL) underargon gas. To the reaction solution was added dropwise 1.63Mn-butyllithium/hexane solution (1.20 mL) at −78° C., and the reactionsolution was stirred at 0° C. for 10 minutes. To the reaction solutionwas added dropwise a mixed solution of(3-methoxymethoxymethyl-cyclobutyl)-acetic acid methyl ester (363 mg) intetrahydrofuran (2.0 mL) at −78° C., which was stirred at −20° C. foradditional 1.5 hours. To the reaction solution was added dropwise 1Mchloro titanium (IV) triisopropoxide/hexane solution (3.70 mL) at −78°C., which was stirred at −78° C. for additional 1 hour. To the reactionsolution was added dropwise a mixed solution of(S)-2-methyl-propane-2-sulfinic acid[1-[3-chloro-4-(3,3-dimethyl-buty1)-phenyl]-eth-(E)-ylidene]-amide (307mg) in tetrahydrofuran (2.0 mL), which was stirred at −78° C. for 4hours. To the reaction solution was added acetic acid (0.212 mL) at −78°C. To the reaction solution were added 10 wt/v % aqueous citric acidsolution and ethyl acetate at room temperature, which was separated. Theorganic layer was washed sequentially with 10 wt/wt % aqueous citricacid solution and aqueous saturated sodium chloride solution, and driedover sodium sulfate. After removing sodium sulfate on a filter, thefiltrate was concentrated under reduced pressure. The resulted residuewas purified through silica gel column chromatography (ethylacetate:hexane=1:2->1:1->2:1) to give the titled compound (429 mg) as adiastereomer mixture.

¹H-NMR (400 MHz, CDCl₃) 0.97-0.98 (m, 9H), 1.28-1.34 (m, 9H), 1.42-1.52(m, 3H), 1.74-1.83 (m, 3H), 1.85-1.91 (m, 1H), 2.01-2.11 (m, 1H),2.28-2.55 (m, 2H), 2.61-2.71 (m, 3H), 2.85-2.96 (m, 1H), 3.29-3.35 (m,5H), 3.53-3.65 (m, 3H), 4.53-4.60 (m, 2H), 5.03-5.28 (m, 1H), 7.12-7.21(m, 2H), 7.41-7.37 (m, 1H)

Step 5(R)-3-Amino-3-[3-chloro-4-(3,3-dimethyl-buty1)-pheny1]-2-(3-hydroxymethyl-cyclobutyl)-butanoicacid methyl ester

(R)-3-[3-Chloro-4-(3,3-dimethyl-butyl)-phenyl]-2-(3-methoxymethoxymethyl-cyclobuty1)-3-((S)-2-methyl-propane-2-sulfinylamino)-butanoicacid methyl ester (315 mg) was mixed with methanol (3.0 mL), and theretowas added 2M hydrogen chloride/methanol solution (0.458 mL) under icecooling. The reaction solution was stirred at room temperature for 21hours, and then thereto were added 2N aqueous sodium hydroxide solution(0.910 mL) and saturated aqueous sodium hydrogen carbonate solutionunder ice cooling. To the reaction solution was added ethyl acetate,which was separated. Then the organic layer was washed with aqueoussaturated sodium chloride solution, and dried over sodium sulfate. Afterremoving sodium sulfate on a filter, the filtrate was concentrated underreduced pressure. The resulted residue was purified through silica gelcolumn chromatography (ethyl acetate:hexane=2:1->4:1->ethylacetate:methanol=20:1) to give a diastereomer compound A of the titledcompound (57.5 mg) and a diastereomer compound B of the titled compound(60.3 mg), respectively.

(Diastereomer Compound a of the Titled Compound)

¹H-NMR (400 MHz, CDCl₃) 0.81-0.89 (m, 1H), 0.97 (s, 9H), 1.39-1.49 (m,7H), 1.93-2.01 (m, 1H), 2.13-2.21 (m, 1H), 2.46-2.53 (m, 1H), 2.64-2.68(m, 2H), 2.79 (d, J=9.27 Hz, 1H), 3.37 (d, J=6.04 Hz, 2H), 3.68 (s, 3H),7.14 (d, J=8.06 Hz, 1H), 7.25 (dd, J=8.06, 2.01 Hz, 1H), 7.47 (d, J=2.01Hz, 1H)

(Diastereomer Compound B of the Titled Compound)

¹H-NMR (400 MHz, CDCl₃) 0.97 (s, 9H), 1.41-1.46 (m, 7H), 2.00-2.15 (m,2H), 2.30-2.41 (m, 1H), 2.63-2.68 (m, 3H), 2.81 (d, J=9.67 Hz, 1H), 3.41(s, 3H), 3.50 (d, J=6.04 Hz, 2H), 7.13 (d, J=8.06 Hz, 1H), 7.22 (dd,J=8.06, 2.01 Hz, 1H), 7.40 (d, J=2.01 Hz, 1H)

Step 6(R)-3-Amino-2-[3-(tert-butyl-dimethyl-silanyloxymethyl)-cyclobutyl]-3-[3-chloro-4-(3,3-dimethyl-butyl)-phenyl]-butanoicacid methyl ester

The diastereomer compound A of(R)-3-amino-3-[3-chloro-4-(3,3-dimethyl-butyl)-phenyl]-2-(3-hydroxymethyl-cyclobutyl)-butanoicacid methyl ester (57.0 mg) was mixed with dimethylformamide (1.0 mL),and thereto were added t-butyldimethylchlorosilane (34.3 mg) andimidazole (15.5 mg) at room temperature. The mixture was stirred for16.5 hours, and then thereto were added ethyl acetate and water, whichwas separated. The organic layer was washed sequentially with water (3times) and aqueous saturated sodium chloride solution, and dried oversodium sulfate. After removing sodium sulfate on a filter, the filtratewas concentrated under reduced pressure. The resulted residue waspurified through silica gel column chromatography (ethylacetate:hexane=1:4) to give a diastereomer compound A of the titledcompound (68.6 mg).

¹H-NMR (400 MHz, CDCl₃) 0.04 (s, 6H), 0.79-0.88 (m, 1H), 0.85 (s, 9H),0.97 (s, 9H), 1.29-1.36 (m, 1H), 1.40 (s, 3H), 1.42-1.50 (m, 3H),1.84-1.92 (m, 1H), 2.06-2.15 (m, 1H), 2.38-2.49 (m, 1H), 2.63-2.67 (m,2H), 2.78 (d, J=9.67 Hz, 1H), 3.31 (d, J=5.64 Hz, 2H), 3.68 (s, 3H),7.13 (d, J=8.06 Hz, 1H), 7.26-7.24 (m, 1H), 7.45 (d, J=2.01 Hz, 1H)

The diastereomer compound B of(R)-3-amino-3-[3-chloro-4-(3,3-dimethyl-butyl)-phenyl]-2-(3-hydroxymethyl-cyclobutyl)-butanoicacid methyl ester (60.0 mg) was treated in a similar way to thediastereomer compound A of(R)-3-amino-3-[3-chloro-4-(3,3-dimethyl-butyl)-phenyl]-2-(3-hydroxymethyl-cyclobutyl)-butanoicacid methyl ester to give a diastereomer compound B of the titledcompound (65.0 mg).

¹H-NMR (400 MHz, CDCl₃) 0.02 (s, 6H), 0.89 (s, 9H), 0.97 (s, 9H),1.38-1.45 (m, 6H), 1.50-1.58 (m, 1H), 1.92-2.03 (m, 2H), 2.24-2.32 (m,1H), 2.57-2.66 (m, 3H), 2.79 (d, J=9.67 Hz, 1H), 3.40 (s, 3H), 3.44 (dd,J=5.64, 1.61 Hz, 2H), 7.12 (d, J=8.06 Hz, 1H), 7.22 (dd, J=8.06, 2.01Hz, 1H), 7.40 (d, J=2.01 Hz, 1H)

Step 7(R)-2-[3-(tert-Butyl-dimethyl-silanyloxymethyl)-cyclobutyl]-3-[3-chloro-4-(3,3-dimethyl-butyl)-phenyl]-3-(4-nitro-phenoxycarbonylamino)-butanoicacid methyl ester

The diastereomer compound A (31.3 mg) and the diastereomer compound B(28.0 mg) of(R)-3-amino-2-[3-(tert-butyl-dimethyl-silanyloxymethyl)-cyclobutyl]-3-[3-chloro-4-(3,3-dimethyl-butyl)-phenyl]-butanoicacid methyl ester were mixed with chloroform (1.5 mL), and thereto wereadded diisopropylethylamine (0.0434 mL) and a solution of chloroformicacid p-nitrophenyl ester (50.4 mg) in chloroform (0.5 mL) at roomtemperature. The reaction solution was stirred for 3 hours, and thenconcentrated under reduced pressure. The resulted residue was purifiedthrough thin layer silica gel column chromatography (ethylacetate:hexane=l:6) to give the titled compound (51.4 mg).

Step 8(R)-2[3-(tert-Butyl-dimethyl-silanyloxymethyl)-cyclobutyl]-3-[3-chloro-4-(3,3-dimethyl-butyl)-phenyl]-3-(3-fluoro-3-methyl-cyclobutyloxycarbonylamino)-butanoicacid methyl ester

(R)-2-[3-(tert-Butyl-dimethyl-silanyloxymethyl)-cyclobutyl]-3-[3-chloro-4-(3,3-dimethyl-butyl)-phenyl]-3-(4-nitro-phenoxycarbonylamino)-butanoicacid methyl ester (51.4 mg) was mixed with chloroform (1.0 mL), andthereto were added 3,3-difluorocyclobutylamine hydrochloride (32.9 mg)and triethylamine (0.0478 mL). The reaction solution was stirred for17.5 hours at 60° C., and then concentrated under reduced pressure. Theresulted residue was purified through silica gel column chromatography(ethyl acetate:hexane=1:8->1:6) to give the titled compound (51.3 mg).

Step 9(R)-5-[3-(tert-Butyl-dimethyl-silanyloxymethyl)-cyclobutyl]-6-[3-chloro-4-(3,3-dimethyl-buty1)-phenyl]-3-(3,3-difluoro-cyclobutyl)-6-methyl-dihydro-pyrimidine-2,4-dione

(R)-2-[3-(tert-Butyl-dimethyl-silanyloxymethyl)-cyclobutyl]-3-[3-chloro-4-(3.3-dimethyl-butyl)-phenyl]-3-(3-fluoro-3-methyl-cyclobutyloxycarbonylamino)-butanoicacid methyl ester (51.3 mg) was mixed with tetrahydrofuran (2.0 mL)under argon gas, and thereto was added potassium t-butoxide (12.8 mg)under ice cooling. The reaction solution was stirred for 40 minutesunder ice cooling, and then thereto was added water. To the reactionsolution was added ethyl acetate, which was separated. The organic layerwas washed sequentially with water and aqueous saturated sodium chloridesolution, and dried over sodium sulfite. After removing sodium sulfateon a filter, the filtrate was concentrated under reduced pressure. Theresulted residue was purified through thin layer silica gelchromatography (ethyl acetate:hexane=1:4) to give the titled compound(36.0 mg) as a mixture of diastereomers.

¹H-NMR (400 MHz, CDCl₃) −0.03-0.04 (m, 6H), 0.85-0.91 (m, 9H), 0.97-0.98(m, 9H), 1.40-1.65 (m, 6H), 1.76-2.23 (m, 3H), 2.54-2.89 (m, 6H),3.05-3.19 (m, 1H), 3.29-3.52 (m, 4H), 4.70-4.98 (m, 1H), 5.40 (brs, 1H),7.28-7.06 (m, 3H)

Step 10(S)-4-[3-Chloro-4-(3,3-dimethyl-butyl)-phenyl]-1-(3,3-difluoro-cyclobutyl)-5-(3-hydroxymethyl-cyclobutyl)-4-methyl-3,4-dihydro-1H-pyrimidin-2-one

Bis(cyclopentadienyl)zirconium (IV) chloride hydride (73.6 mg) was mixedwith tetrahydrofuran (3.0 mL) under argon gas. To the suspension wasadded a solution of(R)-5-[3-(tert-butyl-dimethyl-silanyloxymethyl)-cyclobutyl]-6-[3-chloro-4-(3,3-dimethyl-butyl)-phenyl]-3-(3,3-difluoro-cyclobutyl)-6-methyl-dihydro-pyrimidine-2,4-dione(36.0 mg) in tetrahydrofuran (6.0 ml) at room temperature, which wasthen stirred. To the reaction solution was addedbis(cyclopentadienyl)zirconium (IV) chloridehydride (75.0 mg), and themixture was stirred for 20 hours. To the reaction solution was added 2Nhydrochloric acid (1.0 mL) at room temperature. The reaction solutionwas stirred for 3 days, and then thereto were added ethyl acetate andwater, which was then separated. The organic layer was washedsequentially with saturated aqueous sodium hydrogen carbonate solutionand aqueous saturated sodium chloride solution, and dried over sodiumsulfate. After removing sodium sulfate on a filter, the filtrate wasconcentrated under reduced pressure. The resulted residue was purifiedthrough thin layer silica gel chromatography (methanol:chloroform=1:15)to give the titled compound (10.6 mg).

¹H-NMR (400 MHz, CDCl₃) 0.98 (s, 9H), 1.34-1.47 (m, 3H), 1.58-1.70 (m,5H), 2.09-2.28 (m, 2H), 2.39-2.48 (m, 1H), 2.65-2.69 (m, 2H), 2.76-2.89(m, 2H), 2.93-3.03 (m, 2H), 3.49 (d, J=5.64 Hz, 2H), 4.76-4.70 (m, 1H),4.87 (s, 1H), 5.89 (d, J=1.21 Hz, 1H), 7-17 (d, J=8.06 Hz, 1H), 7.20(dd, J=8.06, 1.61 Hz, 1H), 7.34 (d, J=1.61 Hz, 1H)

Step 113-[(S)-4-[3-Chloro-4-(3,3-dimethyl-butyl)-phenyl]-1-(3,3-difluoro-cyclobutyl)-4-methyl-2-oxo-1,2,3,4-tetrahydro-pyrimidin-5-yl]-cyclobutanoicacid

(S)-4-[3-Chloro-4-(3,3-dimethyl-butyl)-phenyl]-1-(3,3-difluoro-cyclobutyl)-5-(3-hydroxymethyl-cyclobutyl)-4-methyl-3,4-dihydro-1H-pyrimidin-2-one(10.6 mg) was mixed with chloroform (0.5 ml), and thereto was addedDess-Martin reagent (15.9 mg) under ice cooling. The reaction solutionwas stirred for 20 minutes under ice cooling, and then thereto wereadded 10 wt/v % aqueous sodium sulfite solution and saturated aqueoussodium hydrogen carbonate solution, then ethyl acetate. Afterseparation, the organic layer was washed sequentially with saturatedaqueous sodium hydrogen carbonate solution and aqueous saturated sodiumchloride solution, and dried over sodium sulfate. After removing sodiumsulfate on a filter, the filtrate was concentrated under reducedpressure. The residue was mixed with t-butanol (0.7 mL) and acetonitrile(1.4 mL), and thereto were added 1M aqueous sodium dihydrogenphosphatesolution (0.22 mL) and an aqueous solution (0.25 mL) of2-methyl-2-butene, sodium chlorite (3.8 mg) at room temperature. Thereaction solution was stirred for 15.5 hours at room temperature, andthen thereto were added sequentially 10 wt/v % aqueous sodium sulfitesolution and 2N hydrochloric acid, then ethyl acetate. After separation,the organic layer was washed with aqueous saturated sodium chloridesolution, and dried over sodium sulfate. After removing sodium sulfateon a filter, the filtrate was concentrated under reduced pressure. Theresulted residue was purified through thin layer silica gel columnchromatography (methanol:chloroform=1:10) to give the titled compound(7.5 mg).

Example 258 Step 1 1-(4-Bromo-2-chloro-phenyl)-3-isopropyl-cyclobutanol

4-Bromo-2-chloro-1-iodobenzene (3.68 g) was mixed in tetrahydrofuran(17.8 mL). To the reaction solution was added dropwise 2Misopropylmagnesium chloride/tetrahydrofuran (5.8 mL) at −30° C., and thereaction solution was stirred at −30° C. for 40 minutes. To the reactionsolution were added dropwise 0.6M lanthanum chloride bis(lithiumchloride) complex/tetrahydrofuran (4.5 mL) and then a mixed solution of3-isopropyl-cyclobutanone (1.00 g) in tetrahydrofuran (8.9 mL), and thereaction solution was stirred at −30° C. for 4 hours. To the reactionsolution was added 20% aqueous ammonium chloride solution, which wasthen extracted with tert-butylmethylether. The organic layer was washedsequentially with 20% aqueous ammonium chloride solution, water, and 20%aqueous sodium chloride solution, and dried over magnesium sulfate.After removing magnesium sulfate on a filter, the filtrate wasconcentrated under reduced pressure. The resulted residue was purifiedthrough silica gel column chromatography (ethylacetate:hexane=0:100->10:90) to give the titled compound (2.72 g) as amixture of cis- and trans-isomers.

Step 2 4-Bromo-2-chloro-1-(3-isopropyl-cyclobut-1-enyl)-benzene

1-(4-Bromo-2-chloro-phenyl)-3-isopropyl-cyclobutanol (2.42 g) andpentafluoroanilinium trifluoromethanesulfonate (133 mg) were mixed intoluene (16.0 mL). The reaction solution was stirred at 80° C. for 2hours. The reaction solution was concentrated under reduced pressure,and the resulted residue was purified through silica gel columnchromatography (hexane) to give the titled compound (2.02 g).

¹H-NMR (400 MHz, CDCl₃) 0.95 (d, J=6.70 Hz, 3H), 0.98 (d, J=6.47 Hz,3H), 1.59-1.68 (m, 1H), 2.42-2.52 (m, 2H), 2.91 (dd, J=12.72, 4.39 Hz,1H), 6.74 (s, 1H), 7.12 (d, J=8.32 Hz, 1H), 7.34 (dd, J=8.32, 1.97 Hz,1H), 7.50 (d, J=1.97 Hz, 1H)

Step 3 4-Bromo-2-chloro-1-(3-isopropyl-cyclobutyl)-benzene

4-bromo-2-chloro-1-(3-isopropyl-cyclobut-1-enyl)-benzene (2.02 g) wasmixed in a mixed solution of tetrahydrofuran (10.0 mL) and methanol(10.0 mL). To the reaction solution was added 5 w/w % rhodium/activatedcarbon (203 mg), and the reaction solution was stirred for 3 hours at 1atm under hydrogen gas. After removing rhodium/activated carbon on afilter, the filtrate was concentrated under reduced pressure. Theresulted residue was purified through silica gel column chromatography(hexane) to give the titled compound (1.94 g). The relativeconfigurations of substituents on the cyclobutane ring were estimated ascis-configuration by NOESY measurement.

¹H-NMR (400 MHz, CDCl₃) 0.83 (d, J=6.70 Hz, 6H), 1.37-1.46 (m, 1H),1.59-1.68 (m, 2H), 1.85-1.96 (m, 1H), 2.46-2.54 (m, 2H), 3.39-3.48 (m,1H), 7.11 (d, J=8.27 Hz, 1H), 7.34 (dd, J=8.27, 2.03 Hz, 1H), 7.46 (d,J=2.03 Hz, 1H)

Step 4 1-[3-Chloro-4-(3-isopropyl-cyclobutyl)-phenyl]-ethanone

4-Bromo-2-chloro-1-(3-isopropyl-cyclobutyl)-benzene (1.85 g), palladiumacetate (30 mg) and 1,3-bis(diphenylphosphino)propane (103 mg) weremixed in 2-ethoxyethanol (13.0 mL) under argon gas. The reactionsolution was stirred at room temperature for 10 minutes, and then to thereaction solution were added N,N-diisopropylethylamine (2.8 mL) andethyleneglycol monovinyl ether (1.8 mL). The reaction solution wasstirred at 145° C. for 2.5 hours. To the reaction solution was added 6Mhydrochloric acid (3.2 mL) under ice cooling, and the reaction solutionwas stirred at room temperature overnight. To the reaction solution wasadded water, which was then extracted with tert-butylmethylether. Theorganic layer was washed sequentially with water and 25% aqueous sodiumchloride solution, and dried over magnesium sulfate. After removingmagnesium sulfate on a filter, the filtrate was concentrated underreduced pressure. The resulted residue was purified through silica gelcolumn chromatography (ethyl acetate:hexane=0:100->10:90) to give thetitled compound (1.24 g).

¹H-NMR (400 MHz, CDCl₃) 0.84 (d, J=6.70 Hz, 6H), 1.43 (d, J=34.91 Hz,1H), 1.70 (d, J=36.07 Hz, 2H), 1.94 (d, J=42.08 Hz, 1H), 2.54-2.58 (m,2H), 2.57 (s, 3H), 3.50-3.59 (m, 1H), 7.35 (d, J=7.98 Hz, 1H), 7.80 (dd,J=7.98, 1.74 Hz, 1H), 7.89 (d, J=1.74 Hz, 1H)

Step 53-{(S)-4-[3-Chloro-4-(3-isopropyl-cyclobutyl)-phenyl]-5-isopropyl-4-methyl-2-oxo-3,4-dihydro-2H-pyrimidin-1-yl}-propionicacid

1-[3-Chloro-4-(3-isopropyl-cyclobutyl)-phenyl]-ethanone was treated as astarting material in a similar manner to Example 87 (a method forpreparation using an optically active sulfinamide) Steps 5 to 11 to givethe titled compound (73 mg).

Example 271 Step 1 4-(3,3-Dimethyl-but-1-ynyl)-3-trifluoromethyl-benzoicacid

4-Bromo-3-trifluoromethyl-benzoic acid (5.2 g),bis(triphenylphosphine)palladium (II) dichloride (678 mg), and copperiodide (185 mg) were mixed in N-methylpyrrolidone (32 mL) under argongas. The reaction system was vacuated to replace with argon three times,and then thereto were added diisopropylamine (10.9 mL) and3,3-dimethyl-but-1-yne (3.55 mL). The reaction solution was stirred at60° C. overnight, and then warmed to room temperature, and to thereaction solution was added toluene (30 mL). Then thereto were added 2Maqueous sodium hydroxide solution (12 mL) and water, which wash thenextracted with toluene. The resulted aqueous layer was acidified byadding 6M aqueous hydrochloric acid solution (20 mL), and ethyl acetatewas added thereto, and the mixture was separated. The organic layer waswashed with brine, and then dried over magnesium sulfate. After removingmagnesium sulfate on a filter, the filtrate was concentrated underreduced pressure. The resulted residue was purified through silica gelcolumn chromatography (ethyl acetate:methanol=90:10). Hexane was thenadded to the resulted solid, and the resulted slurry was stirred andthen filtered to give the titled compound (2.4 g). The filtrate wasconcentrated under reduced pressure, and purified through silica gelcolumn chromatography (ethyl acetate:hexane=1:9->10:0) to give thetitled compound (1.47 g).

¹H-NMR (400 MHz, CDCl₃) 1.33 (s, 9H), 7.57-7.62 (m, 1H), 8.12-8.17 (m,1H), 8.32-8.35 (m, 1H)

Step 2 4-(3,3-Dimethyl-butyl)-3-trifluoromethyl-benzoic acid

4-(3,3-Dimethyl-but-1-ynyl)-3-trifluoromethyl-benzoic acid (3.9 g) wasmixed in methanol (40 mL). To the mixed solution was added 5 w/w %platinum/activated carbon (1.16 g), and the reaction solution wasstirred for two days overnight at 1 atm under hydrogen gas. Afterremoving platinum/activated carbon on a filter from the reactionsolution, the filtrate was concentrated under reduced pressure to givethe titled compound (7.32 g).

¹H-NMR (400 MHz, CDCl₃) 0.97 (s, 9H), 1.44-1.52 (m, 2H), 2.76-2.84 (m,2H), 7.39-7.45 (m, 1H), 8.12-8.18 (m, 1H), 8.34 (brs, 1H)

Step 34-(3,3-Dimethyl-butyl)-N-methoxy-N-methyl-3-trifluoromethyl-benzamide

4-(3,3-Dimethyl-butyl)-3-trifluoromethyl-benzoic acid, a crude product,(3.78 g), N,O-dimethylhydroxylamine hydrochloride (1.48 g),1-hydroxybenzotriazolemonohydrate (211 mg), and sodium hydrogencarbonate (1.28 g) were mixed in N,N-dimethylformamide (22 mL). Thenthereto was added WSC·HCl (3.04 g), and the mixture was stirred at roomtemperature for 3 hours and then left to stand at room temperatureovernight. To the reaction solution were added water, hexane, and ethylacetate, which was then separated, and then the aqueous layer wasextracted with ethyl acetate twice. After azeotropy of the organic layerwith a denatured ethanol solution, the resulted residue was purifiedthrough silica gel chromatography (ethyl acetate:hexane=8:92->1:1) togive the titled compound (4.29 g).

¹H-NMR (400 MHz, CDCl₃) 0.96 (s, 9H), 1.44-1.50 (m, 2H), 2.72-2.79 (m,2H), 3.36 (s, 3H), 3.54 (s, 3H), 7.31-7.36 (m, 1H), 7.76-7.81 (m, 1H),7.95-7.98 (m, 1H)

Step 4 1-[4-(3,3-Dimethyl-butyl)-3-trifluoromethyl-phenyl]-ethanone

4-(3,3-Dimethyl-butyl)-N-methoxy-N-methyl-3-trifluoromethyl-benzamide(4.29 g) was mixed in tetrahydrofuran (25 mL). To the reaction solutionwas added dropwise 0.91M methylmagnesium bromide/tetrahydrofuransolution (22.3 mL) under ice cooling, and the reaction solution wasstirred under ice cooling for 40 minutes. To the reaction solution wereadded dropwise 1M hydrochloric acid (32 mL) and water under ice cooling,and then thereto was added ethyl acetate. After the mixed solution wasseparated, the aqueous layer was extracted with ethyl acetate. Theresulted organic layer was dried over magnesium sulfate. After removingmagnesium sulfate on a filter, the filtrate was concentrated underreduced pressure to give the titled compound (3.6 g).

Step 54-{(S)-4-[4-(3,3-Dimethyl-butyl)-3-trifluoromethyl-phenyl]-5-isopropyl-4-methyl-2-oxo-3,4-dihydro-2H-pyrimidin-1-yl}-benzoicacid

1-[4-(3,3-Dimethyl-butyl)-3-trifluoromethyl-phenyl]-ethanone was treatedas a starting material in a similar manner to Example 87 (a method forpreparation using an optically active sulfinamide) Steps 5 to 11 to givethe titled compound (29 mg).

Example 281 Step 1(R)-2-(tert-Butyl-diphenyl-silanyloxymethyl)-1-[3-chloro-4-(3,3-dimethyl-butyl)-phenyl]-1,3-dimethyl-butylamine

(R)-3-Amino-3-[3-chloro-4-(3,3-dimethyl-butyl)-phenyl]-2-isopropyl-butan-1-ol(1.98 g) obtained according to Example 159 (a method for preparationusing an optically active sulfinamide) Steps 1 to 2 was mixed withdimethylformamide (50 ml), and to the mixed solution were mixedchloro-t-butyldiphenylsilane (2.36 ml) and imidazole (620 mg) under icecooling. The reaction solution was stirred at room temperature for 20hours. To the reaction solution were added ethyl acetate and water,which was then separated. The organic layer was washed with water andaqueous saturated sodium chloride solution, and dried over sodiumsulfate. After removing sodium sulfate on a filter, the reactionsolution was concentrated under reduced pressure, and the resultedresidue was purified through silica gel column chromatography (ethylacetate:n-hexane) to give the titled compound (2.77 g).

¹H-NMR (400 MHz, CDCl₃) 0.79 (d, J=7.25 Hz, 3H), 0.81 (d. J=7.25 Hz,3H), 0.98 (s, 9H), 1.06 (s, 9H), 1.37 (s, 3H), 1.43-1.47 (m, 2H),1.68-1.75 (m, 1H), 1.79-1.82 (m, 1H), 2.62-2.67 (m, 2H), 3.81 (d, J=5.24Hz, 2H), 7.10 (d, J=8.06 Hz, 1H), 7.18 (dd, J=8.06, 2.01 Hz, 1H),7.37-7.46 (m, 7H), 7.69-7.66 (m, 4H)

Step 2 6-(4-Nitro-phenoxycarbonylamino)-nicotinic acid methyl ester

6-Amino-nicotinic acid methyl ester (100 mg) was mixed withdichloromethane (5.0 mL) and tetrahydrofuran (3.0 mL). To the mixedsolution were added p-nitrophenyl chloroformate (146 mg) and pyridine(0.0798 mL) under ice cooling, which was then stirred for 1 hour. Themixture was stirred at room temperature for 15 minutes, and then a solidwas filtered. The resulted solid was washed sequentially with water,tetrahydrofuran, and n-hexane, and then dried under reduced pressure togive the titled compound (57.3 mg).

¹H-NMR (400 MHz, DMSO-D₆) 3.76 (s, 3H), 6.45 (dd, J=8.87, 0.81 Hz, 1H),6.93 (td, J=6.35, 3.90 Hz, 2H), 7.82 (dd, J=8.87, 2.82 Hz, 1H), 8.12(td, J=6.35, 3.90 Hz, 2H), 8.50 (dd, J=2.42, 0.81 Hz, 1H), 11.04 (s, 1H)

Step 36-(3-{(R)-2-(tert-Butyl-diphenyl-silanyloxymethyl)-1-[3-chloro-4-(3,3-dimethyl-butyl)-phenyl]-1,3-dimethyl-butyl}-ureido)-nicotinicacid methyl ester

(R)-2-(tert-Butyl-diphenyl-silanyloxymethy1)-1-[3-chloro-4-(3,3-dimethyl-butyl)-phenyl]-1,3-dimethyl-butylamine(71.7 mg) was mixed with chloroform (1.5 ml), and to the mixed solutionwere added 6-(4-nitro-phenoxycarbonylamino)-nicotinic acid methyl ester(57.3 mg) and triethylamine (0.0252 ml) at room temperature. Thereaction solution was stirred at 60° C. for 3 hours, and thenconcentrated. The residue was purified through thin layer silica gelchromatography (chloroform:methanol=20:1) to give the titled compound(105 mg).

¹H-NMR (400 MHz, CDCl₃) 0.97 (s, 9H), 0.99 (s, 9H), 1.04 (d, J=6.85 Hz,3H), 1.21 (d, J=6.85 Hz, 3H), 1.34-1.39 (m, 2H), 1.78 (s, 3H), 1.98-2.01(m, 1H), 2.11-2.18 (m, 1H), 2.53-2.66 (m, 2H), 3.47 (dd, J=10.88, 4.03Hz, 1H), 3.67 (dd, J=10.88, 8.87 Hz, 1H), 3.93 (s, 3H), 6.36 (d, J=8.87Hz, 1H), 7.01 (d, J=8.06 Hz, 1H), 7.07 (dd, J=8.06, 1.61 Hz, 1H),7.26-7.30 (m, 3H), 7.33-7.42 (m, 4H), 7.48 (dd, J=8.06, 1.61 Hz, 2H),7.57 (dd, J=7.66, 1.61 Hz, 2H), 8.03 (dd, J=8.87, 2.01 Hz, 111), 8.66(s, 111), 8.73 (d, J=2.01 Hz, 1H), 10.05 (s, 1H)

Step 46-(3-{(R)-[3-Chloro-4-(3,3-dimethyl-butyl)-phenyl]-2-hydroxymethyl-1,3-dimethyl-butyl}-ureido)-nicotinicacid methyl ester

6-(3-{(R.)-2-(tert-Butyl-diphenyl-silanyloxymethyl)-[3-chloro-4-(3,3-dimethyl-butyl)-phenyl]-1,3-dimethyl-butyl}-ureido)-nicotinicacid methyl ester (105 mg) was mixed with tetrahydrofuran (1.0 ml). Tothe mixed solution was added at room temperature an 1M solution oftetrabutylammonium fluoride in tetrahydrofuran (0.191 ml). The mixturewas stirred for 15 hours at room temperature, and then concentrated. Theresidue was purified through thin layer silica gel column chromatography(chloroform:methanol=20:1) to give the titled compound (62.0 mg).

¹H-NMR (400 MHz, CDCl₃) 0.93 (d, J=6.85 Hz, 3H), 0.96 (s, 9H), 1.15 (d,J=6.85 Hz, 3H), 1.43 (dd, J=8.87, 8.46 Hz, 2H), 1.87-1.90 (m, 1H), 1.92(s, 3H), 2.12-2.19 (m, 1H), 2.58-2.71 (m, 2H), 3.61, −3.72 (m, 2H), 3.93(s, 3H), 6.39 (d, J=8.46 Hz, 1H), 7.16 (d, J=8.06 Hz, 1H), 7.23 (dd,J=8.06, 2.01 Hz, 1H), 7.39 (d, J=2.01 Hz, 1H), 8.05 (dd, 3=8.46, 2.42Hz, 1H), 8.79 (d, J=2.42 Hz, 1H), 8.97 (s, 1H), 10.20 (s, 1H)

Step 56-{(S)-4-[3-Chloro-4-(3,3-dimethyl-butyl)-phenyl]-5-isopropyl-4-methyl-2-oxo-3,4-dihydro-2H-pyrimidin-1-yl}-nicotinicacid methyl ester

6-(3-{(R)-1-[3-Chloro-4-(3,3-dimethyl-butyl)-phenyl]-2-hydroxymethyl-1,3-butyl}-ureido)-nicotinicacid methyl ester (62.0 mg) and iodobenzene diacetate (43.6 mg) weremixed in dichloromethane (1.0 mL). To the reaction solution was added2,2,6,6-tetramethylpiperidine 1-oxyl free radical (1.9 mg) under icecooling, and the reaction solution was stirred at room temperature for18 hours. To the reaction solution was added trifluoroacetic acid(0.0182 mL) under ice cooling, which was then stirred at roomtemperature for 4.5 hours. To the reaction solution were added aqueoussodium sulfite solution and then aqueous sodium hydrogen carbonatesolution at room temperature. The resulted mixed solution was extractedwith ethyl acetate. The organic layer was washed with aqueous saturatedsodium chloride solution, and dried over sodium sulfate. After removingsodium sulfate on a filter, the filtrate was concentrated under reducedpressure. The resulted residue was purified through thin layer silicagel column chromatography (chloroform:methanol=20:1).

The resulted compound was mixed with chloroform, and thereto was addedtrifluoroacetic acid. The reaction solution was stirred at 50° C. for3.5 hours, and then concentrated, The residue was mixed with ethylacetate, and washed sequentially with aqueous sodium hydrogen carbonatesolution, and aqueous saturated sodium chloride solution, and dried oversodium sulfate. After removing sodium sulfate on a filter, the filtratewas concentrated under reduced pressure to give the titled compound(22.5 mg).

¹H-NMR (400 MHz, CDCl₃) 0.84 (d, J=6.85 Hz, 3H), 0.98 (s, 9H), 1.17 (d,J=6.85 Hz, 3H), 1.42-1.46 (m, 2H), 1.81 (s, 3H), 1.95-2.02 (m, 1H),2.65-2.69 (m, 2H), 3.95 (s, 3H), 5.22 (s, 1H), 7.19 (d, J=8.06 Hz, 1H),7.30 (dd, J=8.06, 2.01 Hz, 1H), 7.39 (s, 1H), 7.44 (d, J=2.01 Hz, 1H),8.12 (d, J=8.87 Hz, 1H), 8.25 (dd, J=8.87, 2.42 Hz, 1H), 9.01 (d, J=2.42Hz, 1H)

Step 66-{(S)-4-[3-Chloro-4-(3,3-dimethyl-butyl)-phenyl]-5-isopropyl-4-methyl-2-oxo-3,4-dihydro-2H-pyrimidin-1-yl}-nicotinicacid hydrochloride

6-{(S)-4-[3-Chloro-4-(3,3-dimethyl-butyl)-phenyl]-5-isopropyl-4-methyl-2-oxo-3,4-dihydro-2H-pyrimidin-1-yl}-nicotinicacid methyl ester (22.5 mg) was mixed with ethanol (1.0 mL) andtetrahydrofuran (0.25 mL). To the reaction solution was added dropwise2M aqueous sodium hydroxide solution (0.0465 mL) at room temperature,and the reaction solution was stirred at room temperature for 14.5hours. To the reaction solution was added 2M hydrochloric acid at roomtemperature, which was then concentrated. To the residue was added amixed solution of ethyl acetate and methanol (ethylacetate:methanol=10:1), and an insoluble was removed on a filter. Thefiltrate was concentrated to give the titled compound (22.0 mg).

Examples 263 and 264

According to the following reaction scheme, the compounds of Examples263 and 264 were prepared. In the reaction scheme,3-[(S)-4-(4-bromo-3-chloro-phenyl)-5-isopropyl-4-methyl-2-oxo-3,4-dihydro-2H-pyrimidin-1-yl]-propionicacid ethyl ester was synthesized in Example 116 Step 6.

In the formula, GrubbsCat.2nd means a second-generation Grubbs catalyst,(1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(phenylmethylene)(tricyclohexylphosphine)-ruthenium.

Example 273

The compound of Example 273 was prepared using an optically activesulfinic acid as follows.

Example 292

The compound of Example 292 was prepared according to the followingreaction scheme.

Examples 293 and 294

The compounds of Examples 293 and 294 were prepared using the bromoproduct obtained in Step 10 of the method using Cleisen reaction inExample 116 and 2-methyl-but-3-yn-2-ol.

Example 296

The compound of Example 296 was prepared according to the followingreaction scheme.

Example 298

The compound of Example 298 was prepared according to the followingreaction scheme. In the following reaction scheme,3-[(S)-4-(4-bromo-3-chloro-phenyl)-5-isopropyl-4-methyl-2-oxo-3,4-dihydro-2H-pyrimidin-1-yl]-propionicacid ethyl ester was synthesized in Example 116 Step 6.

Example 316

The compound of Example 316 was prepared using(3,3-difluoro-cyclobutyl)-acetic acid methyl ester as follows accordingto the method of Example 229.

Example 320

The compound of Example 320 was prepared using(3,3-difluoro-cyclobutyl)-acetic acid methyl ester as follows accordingto the method of Example 271.

According to the method of Example 87, Example 116, Example 154 orExample 159 using an optically active sulfinic acid amide (i.e.,(S)-(−)-2-methyl-propane-2-sulfinic acid amide), the following Examplecompounds were prepared.

-   -   Example 38, Example 113, Example 125, Example 126,    -   Example 127, Example 137, Example 140, Example 147,    -   Example 150, Example 157, Example 158. Example 161,    -   Example 162, Example 163, Example 164, Example 165,    -   Example 173, Example 175, Example 176, Example 177,    -   Example 178, Example 179, Example 183, Example 185,    -   Example 189

According to the method using the reaction of an optically activesulfinic acid amide the following Example compounds were prepared.

-   -   Example 190 to Example 357, other than Example 190, Example 191,        Example 197, Example 198, Example 199, Example 200, Example 205,        Example 212, Example 213, and Example 312

According to the method of Example 87, Example 116 or Example 130 usingCleisen reaction, the following Example compounds were prepared.

-   -   Example 9, Example 12, Example 13, Example 14,    -   Example 15, Example 16, Example 17, Example 18,    -   Example 19, Example 20, Example 21, Example 22,    -   Example 23, Example 24, Example 25, Example 26,    -   Example 27, Example 28, Example 29, Example 30,    -   Example 31, Example 32, Example 33, Example 34,    -   Example 35, Example 36, Example 37, Example 38,    -   Example 39, Example 40, Example 41, Example 42,    -   Example 43, Example 44, Example 45, Example 46,    -   Example 47, Example 48, Example 49, Example 50,    -   Example 51, Example 52, Example 53, Example 54,    -   Example 55, Example 56, Example 57, Example 58,    -   Example 59, Example 60, Example 61, Example 63,    -   Example 64, Example 65, Example 66, Example 67,    -   Example 68, Example 69, Example 70, Example 71,    -   Example 72, Example 73, Example 74, Example 75,    -   Example 76, Example 77, Example 78, Example 79,    -   Example 80, Example 81, Example 82, Example 83,    -   Example 84, Example 85, Example 86, Example 88,    -   Example 89, Example 90, Example 91, Example 92,    -   Example 93, Example 94, Example 95, Example 96,    -   Example 97, Example 98, Example 99, Example 100,    -   Example 103, Example 104, Example 105, Example 106,    -   Example 107, Example 108, Example 109, Example 110,    -   Example 111, Example 112, Example 114, Example 115,    -   Example 117, Example 118, Example 119, Example 120,    -   Example 121, Example 122, Example 123, Example 124,    -   Example 128, Example 129, Example 131, Example 132,    -   Example 133, Example 134, Example 135, Example 136,    -   Example 138, Example 139, Example 141, Example 142,    -   Example 143, Example 1.44, Example 145, Example 146,    -   Example 148, Example 149, Example 151, Example 152,    -   Example 153, Example 155, Example 156, Example 160,    -   Example 166, Example 167, Example 168, Example 169,    -   Example 170, Example 171, Example 172, Example 174,    -   Example 180, Example 181, Example 182, Example 184,    -   Example 186, Example 188

According to the method using the Cleisen reaction, the followingExample compounds were prepared.

-   -   Example 190, Example 191, Example 197, Example 198,    -   Example 199, Example 200, Example 205, Example 312

When an Example compound is an optically active product, a desirableenantiomer was obtained by a chiral column separation and purificationof a racemate intermediate (e.g. an ethyl ester intermediate).

For example, the following example is illustrated (see Example 87, Steps13 and 14, a method for preparation using Cleisen reaction).

Each absolute configuration of each enantiomer was estimated on thebasis of the followings:

-   -   1) A consistency of the retention times in a chiral column of an        optically active product obtained in the method using an        optically active sulfinic acid amide and an optically active        product obtained by the method using Cleisen reaction and a        separation using a chiral column;    -   2) A certain regularity in the retention times in a chiral        column of a methyl ester intermediate or an ethyl ester        intermediate of a compound in the present invention and the        like;    -   3) A certain regularity in the strength of the biological        activity value of each enantiomer of a compound in the present        invention (Test Example 1); and/or    -   4) Results of X-ray structural analysis of a co-crystal of a        compound having an RORγ antagonist activity (i.e. a related        compound having the same 4-phenyl-3,4-dihydro-1H-pyrimidin-2-one        skeleton as the compound of the present invention) and RORγ.

Absolute configurations of parts of Example compounds and theintermediates were determined by single crystal X-ray structuralanalysis.

According to Example 5, the following Example compounds were preparedusing Biginelli reaction.

-   -   Example 1, Example 2, Example 3, Example 4,    -   Example 6, Example 7, Example 8, Example 10,    -   Example 11, Example 62, Example 101, Example 102,    -   Example 187

Chemical structures and structural information of Example compoundsprepared as above are shown in the following tables.

In the tables, i) refers to a stereochemistry of the Example compound,ii) refers to physical data (such as the retention time in a chiralcolumn) and analytical conditions for the Example compound, or physicaldata (such as the retention time in a chiral column) and analyticalconditions for a precursor or intermediate such as an ester of theExample compound.

In the tables,

-   -   “Chiral column IA-3” refers to CHIRALPAK IA-3 0.46 cmφ×15 cm        manufactured by DAICEL Corporation, “Chiral column IC” refers to        CHIRALPAK IC 0.46 cmφ×25 cm manufactured by DAICEL, Corporation,        “Chiral column IF-3” refers to CHIRALPAK IF-3 0.46 cmφ×15 cm        manufactured by DAICEL Corporation, “Chiral column AD-3R” refers        to CHIRALPAKAD-3R 0.46 cmφ×15 cm manufactured by DAICEL        Corporation, and “Chiral column AS-3R” refers to CHIRALPAKAS-3R        0.46 cmφ×15 cm manufactured by DAICEL Corporation.

In the tables, “JAIGEL-ODS-AP-A” refers to an analytical columnJAIGEL-ODS-AP-A, SP-120-10, φ6×25 cm of Japan Analytical Industry Co.,Ltd.

In the tables, for example, “Chiral column IC, IPA/Hexane=3/7, 1 ml/min,Retention time 8.1 min” refers to “Chiral column, Mobile phase, Flowrate, Retention time, used in the measurement”. “IPA” refers toisopropanol. “Hex” or “hexane” refers to n-hexane. “TFA” refers totrifluoroacetic acid.

In the tables, for example, “the optical purity of a methyl ester ofExample 32 was >99% ee” refers to “HPLC analysis using a chiral columnfor a methyl ester, a synthetic precursor, of Example 32 showed that theoptical purity was >99% ee”.

In the tables, HPLC analyses of Examples 38, 87, and 116 using a chiralcolumn were determined with samples synthesized by a method usingCleisen reaction.

The specific optical rotations were determined with samples synthesizedby a method using an optically active sulfinic acid amide.

In the tables, Example 64, Example 278, Example 279, and Example 280 aredifferent with each other and any one of the following isomericcompounds, respectively.

TABLE 1 Example Chemical Structural Formula Structural Information 1

i) Racemate 2

i) Racemate 3

i) Racemate 4

i) Racemate 5

i) Optically active product of Example 1 Enantiomer of Example 6 ii)Optical purity was >99% ee Chiral column AS-3R, H₂O/MeCN/TFA =30/70/0.1, Flow rate 0.5 ml/min, Retention time 13.5 min 6

i) Optically active product of Example 1 Enantiomer of Example 5 ii)Optical purity was >99% ee Chiral column AS-3R, H₂O/MeCN/TFA =30/70/0.1, Flow rate 0.5 ml/min, Retention time 16.7 min 7

i) Racemate 8

i) Racemate 9

i) Racemate 10

i) Optically active product of Example 8 Enantiomer of Example 11 ii)Optical purity was >99% ee Chiral column AS-3R, H₂O/MeCN/TFA =30/70/0.1, Flow rate 0.5 ml/min, Retention time 13.6 min 11

i) Optically active product of Example 8. Optical purity was >99% eeEnantiomer of Example 10 ii) Chiral column AS-3R, H₂O/MeCN/TFA =30/70/0.1, Flow rate 0.5 ml/min, Retention time 12.6 min 12

i) Optically active product of Example 9 Enantiomer of Example 13 ii)Optical purity of methyl ester of Example 12 was >99.9% ee Chiral columnIC, IPA/hexane = 30/70, 1 ml/min, Retention time 7.1 min 13

i) Optically active product of Example 9 Enantiomer of Example 12 ii)Optical purity of methyl ester of Example 13 was >98.9% ee Chiral columnIC, IPA/hexane = 30/70, 1 ml/min, Retention time 8.1 min 14

i) Enantiomer of Example 15 ii) Optical purity was >99% ee Chiral columnAS-3R, H₂O/MeCN/TFA = 40/60/0.1, Flow rate = 0.5 ml/min, Retention time11.4 min 15

i) Enantiomer of Example 14 ii) Optical purity was >99% ee Chiral columnAS-3R, H₂O/MeCN/TFA = 40/60/0.1, Flow rate = 0.5 ml/min, Retention time12.7 min 16

i) Racemate 17

i) Racemate 18

i) Racemate 19

i) Single enantiomer Example 19, Example 20, and Example 21 arediastereomers with each other ii) 96.7% d.e Chiral column IC,IPA/hexane/TFA = 3/7/0.1, 1 ml/min, Retention time 5.8 min, 20

i) Single enantiomer Example 19, Example 20, and Example 21 arediastereomers with each other ii) 96.2% d.e Chiral column IC,IPA/hexane/TFA = 3/7/0.1, 1 ml/min, Retention time 5.3 min 21

i) A mixture of two diastereomers Example 19, Example 20, and Example 21are diastereomer with each other ii) Chiral column IC, IPA/hexane/TFA =1/9/0.I, 1 ml/min, Retention time 12.9 min, 13.3 min 22

i) Racemate 23

i) Racemate 24

i) A mixture of two diastereomers ii) Methyl ester of Example 24analytical condition Chiral column IF-3, hexane/IPA = 90/10, Flow rate 1ml/min, Retention time 8.6 min, 8.7 min 25

i) A mixture of two diastereomers ii) Methyl ester of Example 25analytical condition Chiral column IF-3, hexane/IPA = 90/10, Flow rate 1ml/min, Retention time 12.5 min, 13.3 min 26

i) Racemate 27

i) Racemate 28

i) Racemate 29

i) Racemate 30

i) Racemate 31

i) Enantiomer of Example 32 ii) Optical purity of methyl ester ofExample 31 was >99% ee Chiral column IA-3, hexane/IPA = 80/20, Flow rate1 ml/min, Retention time 3.7 min 32

i) Enantiomer of Example 31 ii) Optical purity of methyl ester ofExample 32 was >99% ee Chiral column IA-3, hexane/IPA = 80/20, Flow rate1 ml/min, Retention time 4.6 min 33

i) A mixture of two diastereomers ii) Chiral column AS-3R, H₂O/MeCN/TFA= 40/60/0.1, 0.5 ml/min, Retention time 12.60 min 34

i) A mixture of two diastereomers ii) Chiral column AS-3R, H₂O/MeCN/TFA= 40/60/0.1, 0.5 ml/min, Retention time 13.25 min, 14.05 min 35

i) Enantiomer of Example 36 ii) Optical purity was >99.5% ee Chiralcolumn IA-3, IPA/Hex/TFA = 5/95/0.1, 1 ml/min, Retention time 4.91 min36

i) Enantiomer of Example 35 ii) Optical purity was >99.5% ee Chiralcolumn IA-3, IPA/Hex/TFA = 5/95/0.1, 1 ml/min, Retention time 8.08 min37

i) Enantiomer of Example 38 ii) 92% ee Chiral column AD-3R,H₂O/MeCN/HCOOH = 30/70/0.1, Flow rate 0.5 ml/min, Retention time 6.5 min38

i) Enantiomer of Example 37 ii) >99% ee Chiral column AD-3R,H₂O/MeCN/HCOOH = 30/70/0.1, Flow rate 0.5 ml/min, Retention time 10.0min [α]_(D) ²⁵ = +106.5° (C = 1.00, MeOH) 39

i) Enantiomer of Example 40 ii) Optical purity of methyl ester ofExample 39 was >99% ee Chiral column IA-3, IPA/Hex/TFA = 10/90/0.1, 1ml/min, Retention time 6.32 min 40

i) Enantiomer of Example 39 ii) Optical purity of methyl ester ofExample 40 was >99% ee Chiral column IA-3, IPA/Hex/TEA = 10/90/0.1, 1ml/min, Retention time 9.27 min 41

i) Enantiomer of Example 42 ii) Optical purity of methyl ester ofExample 41 was >99% ee Chiral column IA-3, hexane/IPA = 90/10, Flow rate1 ml/min, Retention time 4.8 min 42

i) Enantiomer of Example 41 ii) Optical purity of methyl ester ofExample 42 was >99% ee Chiral column IA-3, hexane/IPA = 90/10, Flow rate1 ml/min, Retention time 10.2 min 43

i) Enantiomer of Example 44 ii) Analytical condition of methyl ester ofExample 43 Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min,Retention time 4.0 min 44

i) Enantiomer of Example 43 ii) Analytical condition of methyl ester ofExample 44 Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min,Retention time 4.0 min 45

i) Enantiomer of Example 46 ii) Optical purity of methyl ester ofExample 45 was >99% ee Chiral column IA-3, hexane/IPA = 90/10, Flow rate1 ml/min, Retention time 4.4 min 46

i) Enantiomer of Example 45 ii) Optical purity of methyl ester ofExample 46 was >99% ee Chiral column IA-3, hexane/IPA = 90/10, Flow rate1 ml/min, Retention time 6.7 min 47

i) Enantiomer of Example 48 ii) Optical purity of methyl ester ofExample 47 was >99% ee Chiral column IA-3, hexane/IPA = 90/10, Flow rate1 ml/min, Retention time 5.3 min 48

i) Enantiomer of Example 47 ii) Optical purity of methyl ester ofExample 48 was >99% ee Chiral column IA-3, hexane/IPA = 90/10, Flow rate1 ml/min, Retention time 7.3 min 49

i) Enantiomer of Example 50 ii) Optical purity of methyl ester ofExample 49 was >99% ee Chiral column IA-3, hexane/IPA = 80/20, Flow rate1 ml/min, Retention time 5.3 min 50

i) Enantiomer of Example 49 ii) Optical purity of methyl ester ofExample 50 was >99% ee Chiral column IA-3, hexane/IPA = 80/20, Flow rate1 ml/min, Retention time 7.3 min 51

i) Enantiomer of Example 52 ii) Optical purity of methyl ester was >99%ee Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min, Retentiontime 6.0 min 52

i) Enantiomer of Example 51 ii) Optical purity of methyl ester ofExample 52 was >99% ee Chiral column IA-3, hexane/IPA = 90/10, Flow rate1 ml/min, Retention time 7.9 min 53

i) Racemate 54

i) Enantiomer of Example 55 ii) Optical purity of methyl ester ofExample 54 was >99% ee Chiral column IA-3, IPA/Hex/TFA = 10/90/0.1, 1ml/min, Retention time 3.65 min 55

i) Enantiomer of Example 54 ii) Optical purity of methyl ester ofExample 55 was >99% ee Chiral column IA-3, IPA/Hex/TFA = 10/90/0.1, 1ml/min, Retention time 6.01 min 56

i) Enantiomer of Example 57 ii) Optical purity of methyl ester ofExample 56 was >99% ee Chiral column IA-3, hexane/IPA = 90/10, Flow rate1 ml/min, Retention time 5.8 min 57

i) Enantiomer of Example 58 ii) Optical purity of methyl ester ofExample 57 was >99% ee Chiral column IA-3, hexane/IPA = 90/10, Flow rate1 ml/min, Retention time 8.5 min 58

i) Enantiomer of Example 59 ii) Optical purity of methyl ester ofExample 57 was >99% ee Chiral column IA-3, hexane/IPA = 90/10, Flow rate1 ml/min, Retention time 5.2 min 59

i) Enantiomer of Example 58 ii) Optical purity of methyl ester was >99%ee Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min, Retentiontime 8.1 min 60

i) Enantiomer of Example 61 ii) Optical purity of methyl ester ofExample 60 was >99% ee Chiral column IA-3, hexane/IPA = 90/10, Flow rate1 ml/min, Retention time 6.1 min 61

i) Enantiomer of Example 60 ii) Optical purity of methyl ester ofExample 61 was >99% ee Chiral column IA-3, hexane/IPA = 90/10, Flow rate1 ml/min, Retention time 9.6 min 62

i) Racemate 63

i) Single enantiomer Stereochemistry of cyclopentane ring not determinedii) Optical purity of methyl ester of Example 63 was >99% ee Chiralcolumn IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min, Retention time 4.3min 64

i) Single enantiomer Stereochemistry of cyclopentane ring not determinedExamples 64, 278, 279, and 280 are a diastereomer with each other ii)Optical purity of methyl ester of Example 64 was >99% ee Chiral columnIA-3, hexane/IPA = 90/10, Flow rate 1 ml/min, Retention time 6.3 minOptical purity of Example 64 was >99% ee Analytical condition of Example64 JAIGEL-ODS-AP-A, MeCN/H₂O/HCO₂H = 90/10/0.1, Flow rate 1 ml/min,Retention time 9.6 min. 65

i) Racemate 66

i) Enantiomer of Example 67 ii) Optical purity of methyl ester ofExample 66 was >98% ee Chiral column IF-3, IPA/Hex/TFA = 10/90/0.1, 1ml/min, Retention time 8.69 min 67

i) Enantiomer of Example 66 ii) Optical purity of methyl ester ofExample 67 was >98% ee Chiral column IF-3, IPA/Hex/TFA = I0/90/0.1, 1ml/min, Retention time 10.26 min 68

i) Enantiomer of Example 69 ii) Optical purity of methyl ester ofExample 68 was >99% ee Chiral column IA-3, hexane/IPA = 90/10, Flow rate1 ml/min, Retention time 5.3 min 69

i) Enantiomer of Example 68 ii) Optical purity of methyl ester ofExample 69 was >99% ee Chiral column IA-3, hexane/IPA = 90/10, Flow rate1 ml/min, Retention time 8.4 min 70

i) Racemate 71

i) Enantiomer of Example 72 ii) Optical purity of methyl ester ofExample 71 was >99% ee Chiral column IA-3, hexane/IPA = 90/10, Flow rate1 ml/min, Retention time 4.2 min 72

i) Enantiomer of Example 71 ii) Optical purity of methyl ester ofExample 72 was >99% ee Chiral column IA-3, hexane/IPA = 90/10, Flow rate1 ml/min, Retention time 6.5 min 73

i) Diastereomer mixture ii) Analytical condition of methyl ester ofExample 73 Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min,Retention time 3.6 min, 4.6 min, 7.0 min, 7.7 min Example 73 wasprepared by hydrolysis of two diastereomer mixtures with 7.0 min and 7.7min of retention times among the isomers. 74

i) Enantiomer of Example 75 ii) Optical purity of methyl ester ofExample 74 was >99% ee Chiral column IA-3, hexane/IPA = 90/10, Flow rate1 ml/min, Retention time 3.8 min 75

i) Enantiomer of Example 74 ii) Optical purity of methyl ester ofExample 75 was >99% ee Chiral column IA-3, hexane/IPA = 90/10, Flow rate1 ml/min, Retention time 5.0 min 76

i) Enantiomer of Example 77 ii) Optical purity of methyl ester ofExample 76 was >99% ee Chiral column IA-3, hexane/IPA = 90/10, Flow rate1 ml/min, Retention time 3.7 min 77

i) Enantiomer of Example 76 ii) Optical purity of methyl ester ofExample 77 was >99% ee Chiral column IA-3, hexane/IPA = 90/10, Flow rate1 ml/min, Retention time 6.1 min 78

i) Enantiomer of Example 79 ii) Optical purity of methyl ester ofExample 78 was >99.5% ee Chiral column IA-3, IPA/Hex/TFA = 10/90/0.1, 1ml/min, Retention time 5.27 min 79

i) Enantiomer of Example 78 ii) Optical purity of methyl ester ofExample 79 was >99.5% ee Chiral column IA-3, IPA/Hex/TFA = 10/90/0.1, 1ml/min, Retention time 9.25 min 80

i) Racemate 81

i) Racemate 82

i) Enantiomer of Example 83 ii) Optical purity of methyl ester ofExample 82 was >99% ee Chiral column IA-3, hexane/IPA = 80/20, Flow rate1 ml/min, Retention time 4.2 min 83

i) Enantiomer of Example 82 ii) Optical purity of methyl ester ofExample 83 was >99% ee Chiral column IA-3, hexane/IPA = 80/20, Flow rate1 ml/min, Retention time 6.3 min 84

i) Racemate 85

i) Racemate 86

i) Enantiomer of Example 87 ii) Optical purity of ethyl ester was >99%ee Analytical condition of ethyl ester of Example 86 Chiral column IA-3,hexane/IPA = 90/10, Flow rate 1 ml/min, Retention time 4.9 min Opticalpurity of Example 86 was >99% ee Analytical condition of Example 86Chiral column AD-3R, H₂O/MeCN/HCOOH = 30/70/0.1, Flow rate 0.5 ml/min,Retention time 6.0 min 87

i) Enantiomer of Example 86 ii) Optical purity of ethyl ester was >99%ee Analytical condition of ethyl ester of Example 87 Chiral column IA-3,hexane/IPA = 90/10, Flow rate 1 ml/min, Retention time 7.1 min Opticalpurity of Example 87 was >99% ee Analytical condition of Example 87Chiral column AD-3R, H₂O/MeCN/HCOOH = 30/70/0.1, Flow rate 0.5 ml/minRetention time 9.0 min [α]_(D) ²⁵ = +112.6° (C = 1.00, MeOH) 88

i) Diastercomer of Example 89 ii) Optical purity of methyl ester ofExample 88 was >99% ee Chiral column IA-3, hexane/IPA = 80/20, Flow rate1 ml/min, Retention time 3.7 min 89

i) Diastercomer of Example 88 ii) Optical purity of methyl ester ofExample 89 was >99% ee Chiral column IA-3, hexane/IPA = 80/20, Flow rate1 ml/min, Retention time 5.6 min 90

i) Racemate 91

i) Enantiomer of Example 92 ii) Optical purity of methyl ester ofExample 91 was >99% ee Chiral column IA-3, hexane/IPA = 80/20, Flow rate1 ml/min, Retention time 4.5 min 92

i) Enantiomer of Example 91 ii) Optical purity of methyl ester ofExample 92 was >99% ee Chiral column IA-3, hexane/IPA = 80/20, Flow rate1 ml/min, Retention time 7.5 min 93

i) Enantiomer of Example 94 ii) Optical purity of methyl ester ofExample 93 was >99% ee Chiral column IA-3, hexane/IPA = 90/10, Flow rate1 ml/min, Retention time 5.3 min 94

i) Enantiomer of Example 93 ii) Optical purity of methyl ester ofExample 94 was >99% ee Chiral column IA-3, hexane/IPA = 90/10, Flow rate1 ml/min, Retention time 6.8 min 95

i) Enantiomer of Example 96 ii) Analytical condition of methyl ester ofExample 95 Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min,Retention time 5.0 min 96

i) Enantiomer of Example 95 ii) Analytical condition of methyl ester ofExample 96 Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min,Retention time 9.7 min 97

i) Enantiomer of Example 98 ii) Optical purity of ethyl ester of Example97 was >99% ee Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1ml/min, Retention time 4.2 min 98

i) Enantiomer of Example 97 ii) Optical purity of ethyl ester of Example98 was >99% ee Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1ml/min, Retention time 6.2 min 99

i) Enantiomer of Example 100 ii) Optical purity of methyl ester ofExample 99 was >99% ee Chiral column IA-3, hexane/IPA = 80/20, Flow rate1 ml/min, Retention time 4.3 min 100

i) Enantiomer of Example 99 ii) Optical purity of methyl ester ofExample 100 was >99% ee Chiral column IA-3, hexane/IPA = 80/20, Flowrate 1 ml/min, Retention time 8.9 min 101

i) Enantiomer of Example 102 ii) Analytical condition of methyl ester ofExample 101 Chiral column IA-3, hexane/IPA = 80/20, Flow rate 1 ml/min,Retention time 7.3 min 102

i) Enantiomer of Example 101 ii) Analytical condition of methyl ester ofExample 102 Chiral column IA-3, hexane/IPA = 80/20, Flow rate 1 ml/min,Retention time 7.9 min 103

i) Enantiomer of Example 104 ii) Optical purity of methyl ester ofExample 103 was >99% ee Chiral column IA-3, hexane/IPA = 90/10, Flowrate 1 ml/min, Retention time 4.7 min 104

i) Enantiomer of Example 103 ii) Optical purity of methyl ester ofExample 104 was >99% ee Chiral column IA-3, hexane/IPA = 90/10, Flowrate 1 ml/min, Retention time 12.4 min 105

i) Racemate 106

i) Racemate 107

i) Enantiomer of Example 108 ii) Optical purity of methyl ester ofExample 107 was >99% ee Chiral column IA-3, hexane/IPA = 80/10, Flowrate 1 ml/min, Retention time 3.4 min The relative configuration ofsubstituents on the cyclobutane ring was estimated as trans-isomer 108

i) Enantiomer of Example 107 ii) Optical purity of methyl ester ofExample 108 was >99% ee Chiral column IA-3, hexane/IPA = 80/10, Flowrate 1 ml/min, Retention time 4.9 min 109

i) Enantiomer of Example 110 ii) Analytical condition of methyl ester ofExample 109 Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min,Retention time 5.7 min 110

i) Enantiomer of Example 109 ii) Analytical condition of methyl ester ofExample 110 Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min,Retention time 9.3 min 111

i) Enantiomer of Example 112 ii) Optical purity of ethyl ester ofExample 111 was 86.6% ee Chiral column IA-3, hexane/IPA = 90/10, Flowrate 1 ml/min, Retention time 3.8 min 112

i) Enantiomer of Example 111 ii) Optical purity of ethyl ester ofExample 112 was 98.8% ee Chiral column IA-3, hexane/IPA = 90/10, Flowrate 1 ml/min, Retention time 4.3 min 113

i) Optically active product (optical purity not determined) 114

i) Racemate 115

i) Enantiomer of Example 116 ii) Optical purity was >99% ee Analyticalcondition of ethyl ester of Example 115 Chiral column IA-3, hexane/IPA =90/10, Flow rate 1 ml/min, Retention time 4.1 min Analytical conditionof Example 115 Chiral column AD-3R, H₂O/MeCN/HCOOH = 30/70/0.1, Flowrate 0.5 ml/min, Retention time 6.0 min 116

i) Enantiomer of Example 115 ii) Optical purity was >99% ee Analyticalcondition of ethyl ester of Example 116 Chiral column IA-3, hexane/IPA =90/10, Flow rate 1 ml/min, Retention time 6.4 min Analytical conditionof Example 116 Chiral column AD-3R, H₂O/MeCN/HCOOH = 30/70/0.1, Flowrate 0.5 ml/min, Retention time 9.2 min [α]_(D) ²⁵ = +106.1° (C = 1.00,MeOH) 117

i) Enantiomer of Example 118 ii) Prepared by hydrolysis of ethyl esterof Example 117 Analytical condition of ethyl ester Chiral column IA-3,hexane/IPA = 90/10, Flow rate 1 ml/min, Retention time 4.1 min 118

i) Enantiomer of Example 117 ii) Synthesized by hydrolysis of ethylester of Example 118 Analytical condition of ethyl ester Chiral columnIA-3, hexane/IPA = 90/10, Flow rate 1 ml/min, Retention time 6.4 min 119

i) Enantiomer of Example 120 ii) Analytical condition of ethyl ester ofExample 119 Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min,Retention time 4.8 min 120

i) Enantiomer of Example 119 ii) Analytical condition of ethyl ester ofExample 120 Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min,Retention time 8.9 min 121

i) Enantiomer of Example 122 ii) Analytical condition of ethyl ester ofExample 121 Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min,Retention time 4.7 min 122

i) Enantiomer of Example 121 ii) Analytical condition of ethyl ester ofExample 122 Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min,Retention time 7.8 min 123

i) Enantiomer of Example 124 ii) Analytical condition of ethyl ester ofExample 123 Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min,Retention time 4.2 min 124

i) Enantiomer of Example 123 ii) Analytical condition of ethyl ester ofExample 124 Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min,Retention time 6.7 min 125

i) Optically active product (optical purity not determined) 126

i) Optically active product (optical purity not determined) 127

i) Optically active product (optical purity not determined) 128

i) Enantiomer of Example 129 ii) Analytical condition of ethyl ester ofExample 128 Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min,Retention time 5.1 min 129

i) Enantiomer of Example 129 ii) Analytical condition of ethyl ester ofExample 128 Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min,Retention time 11.1 min 130

i) Optically active product (optical purity not determined) 131

i) Enantiomer of Example 132 ii) Analytical condition of ethyl ester ofExample 131 Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min,Retention time 5.0 min 132

i) Enantiomer of Example 131 ii) Analytical condition of ethyl ester of1 Example 132 Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1ml/min, Retention time 8.7 min 133

i) Enantiomer of Example 134 ii) Analytical condition of ethyl ester ofExample 133 Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min,Retention time 4.4 min 134

i) Enantiomer of Example 133 ii) Analytical condition of ethyl ester ofExample 134 Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min,Retention time 5.9 min 135

i) Enantiomer of Example 136 ii) Prepared by reduction of ethyl ester ofExample 133 Analytical condition of ethyl ester of Example 135 Chiralcolumn IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min, Retention time 4.4min 136

i) Enantiomer of Example 135 Prepared by reduction of ethyl ester ofExample 134 ii) Analytical condition of ethyl ester of Example 136Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min, Retentiontime 5.9 min 137

i) Optically active product ii) Chiral column AD-3R, H₂O/MeCN/HCOOH =30/70/0.1, Flow rate 0.5 ml/min Retention time 9.2 min [α]_(D) ²⁵ =+113.4° (C = 0.5, MeOH) 138

i) Enantiomer of Example 139 ii) Optical purity of methyl ester ofExample 138 was >99% ee Chiral column IA-3, hexane/IPA = 90/10, Flowrate 1 ml/min, Retention time 4.9 min 139

i) Enantiomer of Example 138 ii) Optical purity of methyl ester ofExample 139 was >99% ee Chiral column IA-3, hexane/IPA = 90/10, Flowrate 1 ml/min, Retention time 8.7 min 140

i) Optically active product (optical purity not determined) 141

i) Enantiomer of Example 142 ii) Analytical condition of ethyl ester ofExample 141 Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min,Retention time 4.1 min 142

i) Enantiomer of Example 141 ii) Analytical condition of ethyl ester ofExample 142 Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min,Retention time 7.5 min 143

i) Enantiomer of Example 144 ii) Analytical condition of ethyl ester ofExample 143 Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min,Retention time 6.0 min 144

i) Enantiomer of Example 143 ii) Analytical condition of ethyl ester ofExample 144 Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min,Retention time 11.1 min 145

i) Enantiomer of Example 146 ii) Optical purity of methyl ester ofExample 145 was >99% ee Chiral column IA-3, hexane/IPA = 90/10, Flowrate 1 ml/min, Retention time 5.1 min 146

i) Enantiomer of Example 145 ii) Optical purity of methyl ester ofExample 146 was >99% ee Chiral column IA-3, hexane/IPA = 90/10, Flowrate 1 ml/min, Retention time 8.6 min 147

i) Optically active product (optical purity not determined) 148

i) Enantiomer of Example 149 ii) Analytical condition of ethyl ester ofExample 148 Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min,Retention time 4.9 min 149

i) Enantiomer of Example 148 ii) Analytical condition of ethyl ester ofExample 149 Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min,Retention time 8.7 min 150

i) Optically active product (optical purity not determined) 151

i) Optically active product ii) Analytical condition of ethyl ester ofExample 151 Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min,Prepared from a fraction with 6.1 min of retention time among fractionswith retention times of 4.2 min and 6.1 min 152

i) Optically active product ii) Analytical condition of ethyl ester ofExample 152 Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min,Retention time 5.1 min 153

i) Optically active product ii) Analytical condition of ethyl ester ofExample 153 Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min,Retention time 7.5 min 154

i) Optically active product ii) Chiral column AD-3R, H₂O/MeCN/HCOOH =30/70/0.1, Flow rate 0.5 ml/min, Retention time 12.1 min [α]_(D) ²⁵ =+141.2° (C = 0.05, MeOH) 155

i) Enantiomer of Example 156 Same absolute configuration as Example 148(prepared by reduction of ethyl ester of Example 148) 156

i) Enantiomer of Example 155 Same absolute configuration as Example 149(prepared by reduction of ethyl ester of Example 149) 157

i) Optically active product (optical purity not determined) 158

i) Optically active product (optical purity not determined) 159

i) Optically active product ii) Chiral column AD-3R, H₂O/MeCN/HCOOH =30/70/0.1, Flow rate 0.5 ml/min, Retention time 16.2 min [α]_(D) ²⁵ =+87.5° (C = 0.25, MeOH) 160

i) Optically active product (optical purity not determined) 161

i) Optically active product (optical purity not determined) 162

i) Optically active product (optical purity not determined) 163

i) Optically active product (optical purity not determined) 164

i) Optically active product (optical purity not determined) 165

i) Optically active product (optical purity not determined) 166

i) Single enantiomer Example 166 and Example 167 are a diastereomer witheach other ii) Ethyl ester of Example 166 was prepared by reduction ofethyl ester of Example 151 (Chiral column IA-3, hexane/IPA = 90/10, Flowrate 1 ml/min, the compound in a fraction with 6.9 min of retentiontime). Prepared from the ethyl ester (Chiral column IA-3, hexane/IPA =80/20, Flow rate 1 ml/min, the compound in a fraction of 3.8 min withretention time) 167

i) Single enantiomer Example 166 and Example 167 are a diastereomer witheach other ii) Ethyl ester of Example 167 was prepared by reduction ofethyl ester of Example 151 (Chiral column IA-3, hexane/IPA = 90/10, Flowrate 1 ml/min, the compound in a fraction with 6.9 min of retentiontime). Prepared from the ethyl ester (Chiral column IA-3, hexane/IPA =80/20, Flow rate 1 ml/min, the compound in a fraction of 4.6 min withretention time) 168

i) Optically active product (optical purity not determined) 169

i) Single enantiomer Stereochemistry of the cyclopropane ring wasestimated as trans-isomer Example 169 and Example 170 are a diastereomerwith each other ii) Analytical condition of ethyl ester of Example 169Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min, Retentiontime 6.7 min 170

i) Single enantiomer Stereochemistry of the cyclopropane ring wasestimated as trans-isomer Example 169 and Example 170 are a diastereomerwith each other ii) Analytical condition of ethyl ester of Example 170Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min, Retentiontime 7.1 min 171

i) Optically active product ii) Analytical condition of ethyl ester ofExample 171 Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min,Prepared from a fraction with 6.6 min of retention time among fractionswith 4.8 min and 6.6 min of retention times. 172

i) Optically active product (optical purity not determined) 173

i) Optically active product (optical purity not determined) 174

i) Single enantiomer Stereochemistry of the cyclopropane ring wasestimated as trans-isomer ii) Analytical condition of ethyl ester ofExample 174 Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min,Retention time 14.5 min 175

i) Optically active product (optical purity not determined) 176

i) Optically active product (optical purity not determined) 177

i) Optically active product (optical purity not determined) 178

i) Optically active product (optical purity not determined) 179

i) Diastereomer mixture of 3-{(S)-4-[3-chloro-4-((S)-1,3,3-trimethyl-butyl)-phenyl]-5-isopropyl-4-methyl-2-oxo- 3,4-dihydro-2H-pyrimidin-1-yl}-propionic acid and 3-{(S)-4-[3-chloro-4-((R)-1,3,3-trimethyl-butyl)-phenyl]-5-isopropyl-4- methyl-2-oxo-3,4-dihydro-2H-pyrimidin-1-yl}-propionic acid 180

i) Optically active product (optical purity not determined) 181

i) Optically active product (optical purity not determined) 182

i) Optically active product (optical purity not determined) 183

i) Optically active product (optical purity not determined) 184

i) Optically active product (optical purity not determined) 185

i) Optically active product (optical purity not determined) 186

i) Optically active product (optical purity not determined) ii) Na saltof Example 77 187

i) Racemate 188

i) Racemate 189

i) Optically active product (optical purity not determined)

TABLE 2 Example Chemical Structural Formula Structural Information 190

i) Optically active product (optical purity not determined) ii)Analytical condition Chiral column IA-3, hexane/IPA = 80/20, Flow rate 1ml/min, Retention time 4.7 min 191

i) Optically active product (optical purity not determined) ii)Analytical condition Chiral column IA-3, hexane/IPA = 80/20, Flow rate 1ml/min, Retention time 10.7 min 192

i) Optically active product (optical purity not determined) 193

i) Optically active product (optical purity not determined) 194

i) Optically active product (optical purity not determined) 195

i) Optically active product (optical purity not determined) 196

i) Optically active product (optical purity not determined) 197

i) Optically active product (optical purity not determined) ii) Opticalpurity of alcohol, a synthetic precursor, was >99% ee Analyticalcondition of alcohol of Example 197 Chiral column IA-3, hexane/IPA =80/20, Flow rate of 1 ml/min, Retention time 6.3 min 198

i) Optically active product (optical purity not determined) 199

i) Optically active product (optical purity not determined) ii) Opticalpurity of alcohol, a synthetic precursor, was >99% ee Analyticalcondition of alcohol of Example 199 Chiral column IA-3, hexane/IPA =80/20, Flow rate of 1 ml/min, Retention time 5.7 min 200

i) Optically active product (optical purity not determined) ii) Opticalpurity of alcohol, a synthetic precursor, was >99% ee Analyticalcondition of alcohol of Example 200 Chiral column IA-3, hexane/IPA =80/20, Flow rate of 1 ml/min, Retention time 6.0 min 201

i) Optically active product (optical purity not determined) 202

i) Optically active product (optical purity not determined) 203

i) Optically active product (optical purity not determined) 204

i) Optically active product (optical purity not determined) 205

i) Optically active product (optical purity not determined) ii)Analytical condition of methyl ester of Example 205 Chiral column IA-3,hexane/IPA = 80/20, Flow rate 1 ml/min, Retention time 8.8 min 206

i) Optically active product (optical purity not determined) 207

i) Optically active product (optical purity not determined) 208

i) Optically active product (optical purity not determined) 209

i) Optically active product (optical purity not determined) 210

i) Optically active product (optical purity not determined) 211

i) Optically active product (optical purity not determined) 212

i) Enantiomer of Example 213 ii) Optical purity of ethyl ester was >99%ee Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min, Retentiontime 5.2 min 213

i) Enantiomer of Example 212 ii) Optical purity of ethyl ester was >99%ee Chiral column IA-3, hexane/IPA = 90/10, Flow rate 1 ml/min, Retentiontime 8.3 min 214

i) Optically active product (optical purity not determined) 215

i) A mixture of two diastereomers 216

i) Optically active product (optical purity not determined) 217

i) A mixture of two diastereomers 218

i) Optically active product (optical purity not determined) 219

i) Optically active product (optical purity not determined) 220

i) Optically active product (optical purity not determined) 221

i) Optically active product (optical purity not determined) 222

i) Optically active product (optical purity not determined) 223

i) A mixture of two diastereomers 224

i) Optically active product (optical purity not determined) 225

i) Optically active product (optical purity not determined) 226

i) Optically active product (optical purity not determined) 227

i) Optically active product (optical purity not determined) 228

i) Optically active product (optical purity not determined) 229

i) Optically active product (optical purity not determined) 230

i) Optically active product (optical purity not determined) 231

i) Optically active product (optical purity not determined) 232

i) Single enantiomer (optical purity not determined) Example 232 andExample 233 are a diastereomer with each other 233

i) Single enantiomer (optical purity not determined) Example 232 andExample 233 are a diastereomer with each other 234

i) Optically active product (optical purity not determined) 235

i) Optically active product (optical purity not determined) 236

i) Optically active product (optical purity not determined) 237

i) Single enantiomer (optical purity not determined) Stereochemistry ofthe pyrrolidine ring was estimated as trans-isomer 238

i) Single enantiomer (optical purity not determined) Stereochemistry ofthe pyrrolidine ring was estimated as trans-isomer 239

i) Single enantiomer (optical purity not determined) Stereochemistry ofthe pyrrolidine ring was estimated as trans-isomer 240

i) Single enantiomer (optical purity not determined) Stereochemistry ofthe pyrrolidine ring was estimated as trans-isomer 241

i) Optically active product (optical purity not determined) 242

i) Single enantiomer (optical purity not determined) Stereochemistry ofthe cyclopentane ring was estimated as trans-isomer Example 242 and 243are a diastereomer with each other 243

i) Single enantiomer (optical purity not determined) Stereochemistry ofthe cyclopentane ring was estimated as trans-isomer Example 242 and 243are a diastereomer with each other 244

i) Single enantiomer (optical purity not determined) Stereochemistry ofthe pyrrolidine ring was estimated as trans-isomer Example 244 and 245are a diastereomer with each other 245

i) Single enantiomer (optical purity not determined) Stereochemistry ofthe pyrrolidine ring was estimated as trans-isomer Example 244 and 245are a diastereomer with each other 246

i) Optically active product (optical purity not determined) 247

i) Optically active product (optical purity not determined) 248

i) Optically active product (optical purity not determined) 249

i) Optically active product (optical purity not determined) 250

i) Optically active product (optical purity not determined) 251

i) Optically active product (optical purity not determined) 252

i) Optically active product (optical purity not determined) 253

i) Optically active product (optical purity not determined) 254

i) Single enantiomer (optical purity not determined) Stereochemistry ofthe cyclohexane ring was estimated as trans-isomer Example 254, Example255, Example 256, and Example 257 are a diastereomer with each other ii)Optical purity of Example 254 was >99% ee Analytical condition ofExample 254 JAIGEL-ODS-AP-A, MeCN/H₂O/HCO₂H = 90/10/0.1, Flow rate 1ml/min, Retention time 10.2 min. 255

i) Single enantiomer (optical purity not determined) Stereochemistry ofthe cyclohexane ring was estimated as cis-isomer Example 254, Example255, Example 256, and Example 257 are a diastereomer with each other ii)Optical purity of Example 255 was >99% ee Analytical condition ofExample 255 JAIGEL-ODS-AP-A, MeCN/H₂O/HCO₂H = 90/10/0.1, Flow rate 1ml/min, Retention time 13.2 min. 256

i) Single enantiomer (optical purity not determined) Stereochemistry ofthe cyclohexane ring was estimated as trans-isomer Example 254, Example255, Example 256, and Example 257 are a diastereomer with each other ii)Optical purity of Example 256 was >99% ee Analytical condition ofExample 256 JAIGEL-ODS-AP-A, MeCN/H₂O/HCO₂H = 90/10/0.1, Flow rate 1ml/min, Retention time 11.7 min. 257

i) Single enantiomer (optical purity not determined) Stereochemistry ofthe cyclohexane ring was estimated as cis-isomer Example 254, Example255, Example 256, and Example 257 are a diastereomer with each other ii)Optical purity of Example 257 was >99% ee Analytical condition ofExample 257 JAIGEL ODS-AP-A, MeCN/H₂O/HCO₂H = 90/10/0.1, Flow rate 1ml/min, Retention time 14.0 min. 258

i) Optically active product (optical purity not determined) 259

i) Optically active product (optical purity not determined) 260

i) Optically active product (optical purity not determined) 261

i) Optically active product (optical purity not determined) 262

i) Optically active product (optical purity not determined) 263

i) Optically active product (optical purity not determined) 264

i) Optically active product (optical purity not determined) 265

i) Optically active product (optical purity not determined) 266

i) Optically active product (optical purity not determined) 267

i) Optically active product (optical purity not determined) 268

i) Optically active product (optical purity not determined) 269

i) Optically active product (optical purity not determined) 270

i) Optically active product (optical purity not determined) 271

i) Optically active product (optical purity not determined) 272

i) Optically active product (optical purity not determined) 273

i) Optically active product (optical purity not determined) 274

i) Optically active product (optical purity not determined) 275

i) Optically active product (optical purity not determined) 276

i) Single enantiomer (optical purity not determined) Stereochemistry ofthe cyclobutane ring not determined 277

i) Single enantiomer (optical purity not determined) Stereochemistry ofthe cyclobutane ring not determined 278

i) Single enantiomer Stereochemistry of the cyclopentane ring notdetermined Examples 64, 278, 279, and 280 are a diastereomer with eachother ii) Optical purity of Example 278 was >99% ee Analytical conditionof Example 278 JAIGEL-ODS-AP-A, MeCN/H₂O/HCO₂H = 90/10/0.1, Flow rate 1ml/min, Retention time 9.1 min. 279

i) Single enantiomer Stereochemistry of the cyclopentane ring notdetermined Examples 64, 278, 279, and 280 are a diastereomer with eachother ii) Optical purity of Example 279 was >99% ee Analytical conditionof Example 279 JAIGEL-ODS-AP-A, MeCN/H₂O/HCO₂H = 90/10/0.1, Flow rate 1ml/min, Retention time 10.4 min. 280

i) Single enantiomer Stereochemistry of the cyclopentane ring notdetermined Examples 64, 278, 279, and 280 are a diastereomer with eachother ii) Optical purity of Example 280 was >99% ee Analytical conditionof Example 280 JAIGEL-ODS-AP-A, MeCN/H₂O/HCO₂H = 90/l 0/0.1, Flow rate 1ml/min, Retention time 10.8 min. 281

i) Optically active product (optical purity not determined) 282

i) Optically active product (optical purity not determined) 283

i) Optically active product (optical purity not determined) 284

i) Optically active product (optical purity not determined) 285

i) Optically active product (optical purity not determined) 286

i) Optically active product (optical purity not determined) 287

i) Optically active product (optical purity not determined) 288

i) Optically active product (optical purity not determined) 289

i) Optically active product (optical purity not determined) 290

i) Optically active product (optical purity not determined) 291

i) Optically active product (optical purity not determined) 292

i) Optically active product (optical purity not determined) 293

i) Optically active product (optical purity not determined) 294

i) Optically active product (optical purity not determined) 295

i) Optically active product (optical purity not determined) 296

i) Optically active product (optical purity not determined) 297

i) Optically active product (optical purity not determined) 298

i) Optically active product (optical purity not determined) 299

i) Single enantiomer Example 299 and Example 300 are a diastereomer witheach other ii) Optical purity of Example 299 was >99% ee Analyticalcondition of Example 299 JAHGEL-ODS-AP-A, MeCN/H₂O/HCO₂H = 80/20/0.1,Flow rate 1 ml/min, Retention time 14.7 min. 300

i) Single enantiomer Example 299 and Example 300 are a diastereomer witheach other ii) Optical purity of Example 300 was >99% ee Analyticalcondition of Example 300 JAIGEL-ODS-AP-A, MeCN/H₂O/HCO₂H = 80/20/0.1,Flow rate 1 ml/min, Retention time 15.3 min. 301

i) Optically active product (optical purity not determined) 302

i) Optically active product (optical purity not determined) 303

i) Optically active product (optical purity not determined) 304

i) Optically active product (optical purity not determined) Diastereomermixture 305

i) Single enantiomer (optical purity not determined) Example 305 andExample 306 are a diastereomer with each other 306

i) Single enantiomer (optical purity not determined) Example 305 andExample 306 are a diastereomer with each other 307

i) Single enantiomer (optical purity not determined) Example 307 andExample 308 are a diastereomer with each other 308

i) Single enantiomer (optical purity not determined) Example 307 andExample 308 are a diastereomer with each other 309

i) Optically active product (optical purity not determined) 310

i) Single enantiomer (optical purity not determined) Example 310 andExample 311 are a diastereomer with each other 311

i) Single enantiomer (optical purity not determined) Stereochemistry ofhydroxyl not determined 312

i) Single enantiomer, >99% ee Analytical condition of Example 312 Chiralcolumn IA-3, hexane/IPA = 80/20, Flow rate 1 ml/min, Retention time 8.8min 313

i) Optically active product (optical purity not determined) 314

i) Optically active product (optical purity not determined) 315

i) Optically active product (optical purity not determined) 316

i) Optically active product (optical purity not determined) 317

i) Optically active product (optical purity not determined) 318

i) Optically active product (optical purity not determined) 319

i) Optically active product (optical purity not determined) 320

i) Optically active product (optical purity not determined) 321

i) Optically active product (optical purity not determined) 322

i) Optically active product (optical purity not determined) 323

i) Optically active product (optical purity not determined) 324

i) Optically active product (optical purity not determined) 325

i) Optically active product (optical purity not determined) 326

i) Optically active product (optical purity not determined) 327

i) Optically active product (optical purity not determined) 328

i) Optically active product (optical purity not determined) 329

i) Optically active product (optical purity not determined) 330

i) Optically active product (optical purity not determined) 331

i) Optically active product (optical purity not determined) 332

i) Optically active product (optical purity not determined) 333

i) Optically active product (optical purity not determined) 334

i) Optically active product (optical purity not determined) 335

i) Optically active product (optical purity not determined) 336

i) Optically active product (optical purity not determined) 337

i) Optically active product (optical purity not determined) 338

i) Optically active product (optical purity not determined) 339

i) Optically active product (optical purity not determined) 340

i) Optically active product (optical purity not determined) 341

i) Optically active product (optical purity not determined) 342

i) Optically active product (optical purity not determined) 343

i) Optically active product (optical purity not determined) 344

i) Single enantiomer (optical purity not determined) Stereochemistry ofthe cyclobutane ring was estimated as cis-isomer 345

i) Optically active product (optical purity not determined) 346

i) Optically active product (optical purity not determined) 347

i) Optically active product (optical purity not determined) 348

i) Optically active product (optical purity not determined) 349

i) Optically active product (optical purity not determined) 350

i) Optically active product (optical purity not determined) 351

i) Single enantiomer (optical purity not determined) Example 351 andExample 352 are a diastereomer with each other 352

i) Single enantiomer (optical purity not determined) Example 351 andExample 352 are a diastereomer with each other 353

i) Optically active product (optical purity not determined) 354

i) Optically active product (optical purity not determined) 355

i) Optically active product (optical purity not determined) 356

i) Optically active product (optical purity not determined) 357

i) Optically active product (optical purity not determined)

In the following table, compounds of Examples 38, 87, and 116 weresynthesized by a preparation method using Claisen reaction and measured.

TABLE 3 MS M + H or M − H or Example ¹H-NMR M − Na + H M − Na − H 1 (400MHz, CDCl₃) 0.98 (s, 9H), 1.06 (s, 9H), 1.88-2.04 437 435 (m, 2H),2.32-2.44 (m, 2H), 3.37-3.44 (m, 1H), 3.61 (s, 2H), 3.69-3.76 (m, 1H),4.82 (d, J = 2.65 Hz, 1H), 5.75-5.81 (m, 1H), 6.09 (s, 1H), 6.82 (d, J =8.60 Hz, 1H), 7.06 (dd, J = 8.49, 2.32 Hz, 1H), 7.23 (d, J = 2.21 Hz,1H) 2 (400 MHz, DMSO-D₆) 0.96 (s, 3H), 1.02 (s, 9H), 1.20 381 379 (s,3H), 3.68 (s, 2H), 4.72 (d, J = 3.24 Hz, 1H), 6.22 (d, J = 5.32 Hz, 1H),7,06 (t, J = 8.21 Hz, 2H), 7.14 (dd, J = 8.32, 2.08 Hz, 1H), 7.26 (d, J= 2.08 Hz, 1H), 8.21 (s, 1H), 12.14 (s, 1H) 3 (400 MHz, CDCl₃) 0.98 (s,9H), 1.14-1.31 (m, 3H), 477 475 1.49-1.59 (m, 2H), 1.64-1.78 (m, 8H),1.90-2.03 (m, 2H), 2.32-2.45 (m, 2H), 3.39-3.46 (m, 1H), 3.68-3.75 (m,1H), 4.03 (t, J = 6.73 Hz, 2H), 4.82 (d, J = 2.65 Hz, 1H), 5.58 (d, J =2.21 Hz, 1H), 6.09 (s, 1H), 6.85 (d, J = 8.38 Hz, 1H), 7.06 (dd, J =8.49, 2.10 Hz, 1H), 7.22 (d, J = 1.98 Hz, 1H) 4 (400 MHz, DMSO-D₆) 0.88(s, 3H), 1,02 (s, 9H), 1.08 395 393 (s, 3H), 2.15 (d, J = 13.87 Hz, 1H),2.29 (d, J = 14.33 Hz, 1H), 3.68 (s, 2H), 4.77 (d, J = 3.24 Hz, 1H),6.15 (d, J = 5.32 Hz, 1H), 7.03 (s, 1H), 7.05 (d, J = 8.55 Hz, 1H), 7.19(dd, J = 8.44, 2.20 Hz, 1H), 7.33 (d, J = 2.08 Hz, 1H), 8.09 (d, J =3.24 Hz, 1H), 11.92 (s, 1H) 5 (400 MHz, CDCl₃) 0.98 (s, 9H), 1.06 (s,9H), 1.90-2.03 437 435 (m, 2H), 2.32-2.45 (m, 2H), 3.38-3.45 (m, 1H),3.61 (s, 2H), 3.68-3.75 (m, 1H), 4.82 (d, J = 2.65 Hz, 1H), 5.62 (brs,1H), 6.09 (s, 1H), 6.82 (d, J = 8.16 Hz, 1H), 7.05 (dd, J = 8.49, 2.32Hz, 1H), 7.23 (d, J = 2.21 Hz, 1H) 6 (400 MHz, CDCl3) 0.99 (s, 9H), 1.07(s, 9H), 1.91-2.03 437 435 (m, 2H), 2.33-2.45 (m, 2H), 3.39-3.46 (m,1H), 3.62 (s, 2H), 3.69-3.76 (m, 1H), 4.82 (d, J = 2.65 Hz, 1H),5.50-5.60 (brm, 1H), 6.09 (s, 1H), 6.83 (d, J = 8.38 Hz, 1H), 7.05 (dd,J = 8.38, 2.21 Hz, 1H), 7.23 (d, J = 2.21 Hz, 1H) 7 (400 MHz, DMSO-D6)0.72 (s, 3H), 0.96 (s, 3H), 1.00 409 407 (s, 9H), 1.37-1.46 (m, 1H),1.61-1.69 (m, 1H), 1.95-2.10 (m, 2H), 3.68 (s, 2H), 4.64 (d, J = 3.24Hz, 1H), 6.08 (d, J = 5.32 Hz, 1H), 7.01 (s, 1H), 7.05 (d, J = 8.44 Hz,1H), 7.19 (dd, J = 8.44, 2.20 Hz, 1H), 7.32 (d, J = 2.31 Hz, 1H), 8.14(d, J = 4.86 Hz, 1H), 11.96 (s, 1H) 8 (400 MHz, CDCl3) 0.97 (s, 9H),0.98 (s, 9H), 1.24-1.30 435 433 (m, 2H), 1.41-1.46 (m, 2H), 1.89-2.02(m, 2H), 2.36-2.40 (m, 2H), 2.62-2.67 (m, 2H), 3.37-3.44 (m, 1H),3.68-3.75 (m, 1H), 4.84 (d, J = 2.87 Hz, 1H), 5.82 (brs, 1H), 6.10 (s,1H), 7.04 (dd, J = 7.72, 1.76 Hz, 1H), 7.16 (d, J = 7.94 Hz, 1H), 7.20(d, J = 1.76 Hz, 1H) 9 (400 MHz, DMSO-D6) 0.73 (d, J = 6.94 Hz, 3H),1.03 437 435 (s, 9H), 1.05 (d, J = 6.94 Hz, 3H), 1.61 (s, 3H), 1.65-1.76(m, 2H), 1.92-1.99 (m, 1H), 2.19 (t, J = 7.40 Hz, 2H), 2.40-2.50 (m,1H), 3.40-3.50 (m, 1H), 3.70 (s, 2H), 6.05 (s, 1H), 6.98 (s, 1H), 7.07(d, J = 8.79 Hz, 1H), 7.27 (dd, J = 8.67, 2.43 Hz, 1H), 7.37 (d, J =2.31 Hz, 1H), 12.07 (s, 1H) 10 (400 MHz, DMSO-D6) 0.92 (s, 9H), 0.93 (s,9H), 1.34-1.38 435 433 (m, 2H), 1.62-1.79 (m, 2H), 2.18 (t, J = 7.40 Hz,2H), 2.57-2.61 (m, 2H), 3.11-3.18 (m, 1H), 3.59-3.66 (m, 1H), 4.76 (d, J= 3.01 Hz, 1H), 6.25 (s, 1H), 7.13 (dd, J = 7.86, 1.62 Hz, 1H), 7.16 (d,J = 3.24 Hz, 1H), 7.25 (d, J = 7.86 Hz, 1H), 7.28 (d, J = 1.85 Hz, 1H),12.05 (brs, 1H) 11 (400 MHz, DMSO-D6) 0.92 (s, 9H), 0.93 (s, 9H),1.34-1.38 435 433 (m, 2H), 1.62-1.78 (m, 2H), 2.18 (t, J = 7.40 Hz, 2H),2.57-2.61 (m, 2H), 3.11-3.18 (m, 1H), 3.59-3.66 (m, 1H), 4.76 (d, J =3.01 Hz, 1H), 6.25 (s, 1H), 7.13 (dd, J = 7.86, 1.62 Hz, 1H), 7.16 (d, J= 3.24 Hz, 1H), 7.25 (d, J = 7.86 Hz, 1H), 7.28 (d, J = 1.85 Hz, 1H),12.05 (brs, 1H) 12 (400 MHz, DMSO-D6) 0.72 (d, J = 6.76 Hz, 3H), 1.00437 435 (d, J = 13.28 Hz, 9H), 1.04 (d, J = 6.76 Hz, 3H), 1.60 (s, 3H),1.66-1.73 (m, 2H), 1.95 (dd, J = 13.52, 6.76 Hz, 1H), 2.19 (t, J = 7.49Hz, 2H), 3.27-3.34 (m, 1H), 3.41-3.48 (m, 1H), 3.69 (s, 2H), 6.04 (s,1H), 6.97 (s, 1H), 7.06 (d, J = 8.69 Hz, 1H), 7.26 (dd, J = 8.57, 2.29Hz, 1H), 7.37 (d, J = 2.41 Hz, 1H), 12.06 (s, 1H) 13 (400 MHz, DMSO-D6)0.72 (d, J = 7.00 Hz, 3H), 1.02 437 435 (s, 9H), 1.04 (t, J = 5.80 Hz,3H), 1.60 (s, 3H), 1.66-1.73 (m, 2H), 1.91-1.97 (m, 1H), 2.19 (t, J =7.49 Hz, 2H), 3.27-3.34 (m, 1H), 3.41-3.48 (m, 1H), 3.69 (s, 2H), 6.04(s, 1H), 6.97 (s, 1H), 7.06 (d, J = 8.69 Hz, 1H), 7.26 (dd, J = 8.57,2.29 Hz, 1H), 7.37 (d, J = 2.41 Hz, 1H), 12.06 (s, 1H) 14 (400 MHz,DMSO-D6) 0.71 (d, J = 6.94 Hz, 3H), 0.95 435 433 (s, 9H), 1.04 (d, J =6.70 Hz, 3H), 1.36-1.40 (m, 2H), 1.61 (s, 3H), 3.66-1.73 (m, 2H),1.94-2.01 (m, 1H), 2.17 (t, J = 7.63 Hz, 2H), 2.56-2.66 (m, 2H),3.25-3.35 (m, 1H), 3.41-3.48 (m, 1H), 6.05 (s, 1H), 7.01 (s, 1H), 7.26(dd, J = 7.98, 1.73 Hz, 1H), 7.29 (d, J = 8.09 Hz, 1H), 7.35 (d, J =1.62 Hz, 1H), 12.08 (s, 1H) 15 (400 MHz, DMSO-D6) 0.71 (d, J = 6.94 Hz,3H), 0.94 435 433 (s, 9H), 1.04 (d, J = 6.70 Hz, 3H), 1.36-1.40 (m, 2H),1.61 (s, 3H), 1.65-1.73 (m, 2H), 1.94-2.01 (m, 1H), 2.17 (t, J = 7.40Hz, 2H), 2.60-2.67 (m, 2H), 3.25-3.35 (m, 1H), 3.41-3.48 (m, 1H), 6.05(s, 1H), 7.01 (s, 1H), 7.26 (dd, J = 7.98, 1.73 Hz, 1H), 7.29 (d, J =8.09 Hz, 1H), 7.35 (d, J = 1.62 Hz, 1H), 12.08 (s, 1H) 16 (400 MHz,DMSO-D6) 0.76 (d, J = 7.00 Hz, 3H), 1.01 449 447 (s, 9H), 1.07 (d, J =6.40 Hz, 3H), 1.60 (s, 3H), 1.98-2.05 (m, 1H), 2.22-2.31 (m, 2H),2.35-2.40 (m, 2H), 2.70-2.78 (m, 1H), 3.69 (s, 2H), 4.65-4.74 (m, 1H),6.26 (s, 1H), 7.06 (s, 1H), 7.09 (s, 1H), 7.24 (dd, J = 8.69, 2.41 Hz,1H), 7.34 (d, J = 2.41 Hz, 1H), 12.22 (s, 1H) 17 (400 MHz, DMSO-D6) 0.78(d, J = 7.49 Hz, 3H), 1.03 449 447 (s, 9H), 1.09 (d, J = 6.76 Hz, 3H),1.60 (s, 3H), 1.95-2.02 (m, 1H), 2.24-2.30 (m, 2H), 2.46-2.54 (m, 2H),2.88-2.90 (m, 1H), 3.69 (s, 2H), 4.92-5.01 (m, 1H), 6.32 (s, 1H), 7.07(t, J = 4.35 Hz, 2H), 7.24 (dd, J = 8.57, 2.29 Hz, 1H), 7.33 (d, J =2.17 Hz, 1H), 12.25 (s, 1H) 18 (400 MHz, DMSO-D6) 0.71 (d, J = 6.76 Hz,3H), 1.01 451 449 (s, 9H), 1.03 (d, J = 7.00 Hz, 3H), 1.47-1.48 (m, 4H),1.60 (s, 3H), 1.91-1.98 (m, 1H), 2.24 (t, J = 6.64 Hz, 2H), 3.25-3.32(m, 1H), 3.41-3.44 (m, 1H), 3.69 (s, 2H), 6.05 (s, 1H), 6.93 (s, 1H),7.06 (d, J = 8.69 Hz, 1H), 7.26 (dd, J = 8.69, 2.41 Hz, 1H), 7.36 (d, J= 2.41 Hz, 1H), 11.99 (s, 1H) 19 (400 MHz, DMSO-D6) 0.70 (d, J = 6.94Hz, 3H), 1.00 451 449 (s, 9H), 1.02 (d, J = 6.70 Hz, 4H), 1.08 (d, J =6.94 Hz, 3H), 1.47 (td, J = 13.76, 7.32 Hz, 1H), 1.58 (s, 3H), 1.79 (td,J = 13.70, 7.24 Hz, 1H), 1.89-1.95 (m, 1H), 2.28 (dt, J = 16.49, 4.74Hz, 1H), 3.32-3.43 (m, 1H), 3.68 (s, 2H), 6.02 (s, 1H), 6.95 (s, 1H),7.05 (d, J = 8.79 Hz, 1H), 7.25 (dd, J = 8.55, 2.31 Hz, 1H), 7.35 (d, J= 2.31 Hz, 1H), 12.11 (s, 1H) 20 (400 MHz, DMSO-D6) 0.71 (d, J = 6.70Hz, 3H), 1.00 451 449 (s, 9H), 1.02 (d, J = 6.70 Hz, 3H), 1.07 (d, J =6.94 Hz, 3H), 1.47-1.50 (m, 1H), 1.58 (s, 3H), 1.75-1.79 (m, 1H),1.95-1.97 (m, 1H), 2.26-2.28 (m, 1H), 3.20-3.27 (m, 1H), 3.47-3.54 (m,1H), 3.67 (s, 2H), 6.01 (s, 1H), 6.96 (s, 1H), 7.04 (d, J = 8.79 Hz,1H), 7.24 (dd, J = 8.55, 2.3 1 Hz, 1H), 7.35 (d, J = 2.31 Hz, 1H), 12.11(s, 1H) 21 (400 MHz, DMSO-D6) 0.70 (dd, J = 6.94, 3.24 Hz, 3H), 451 4491.00 (s, 9H), 1.02 (d, J = 7.40 Hz, 3H), 1.07 (dd, J = 6.94, 4.16 Hz,3H), 1.42-1.53 (m, 1H), 1.58 (s, 3H), 1.73-1.84 (m, 1H), 1.89-1.98 (m,1H), 2.23-2.33 (m, 1H), 3.17-3.57 (m, 2H), 3.68 (s, 2H), 6.02 (d, J =3.70 Hz, 1H), 6.96 (d, J = 4.86 Hz, 1H), 7.05 (dd, J = 8.67, 2.20 Hz,1H), 7.25 (dt, J = 8.79, 2.14 Hz, 1H), 7.35 (d, J = 2.31 Hz, 1H), 12.11(s, 1H) 22 (400 MHz, DMSO-D6) 0.94 (s, 9H), 0.94 (s, 9H), 1.36-1.40 449447 (m, 2H), 1.70-1.72 (m, 2H), 1.78 (s, 3H), 2.19 (t, J = 7.46 Hz, 2H),2.60-2.64 (m, 2H), 3.26-3.28 (m, 1H), 3.48-3.55 (m, 1H), 6.23 (s, 1H),6.85 (s, 1H), 7.27 (s, 2H), 7.36 (s, 1H), 12.09 (brs, 1H) 23 (400 MHz,DMSO-D6) 0.82 (s, 9H), 0.94 (s, 9H), 1.35-1.39 463 461 (m, 2H), 1.54 (s,3H), 1.65-1.69 (m, 2H), 1.79 (d, J = 4.16 Hz, 2H), 2.13 (t, J = 7.46 Hz,2H), 2.59-2.63 (m, 2H), 3.25-3.27 (m, 1H), 3.43-3.50 (m, 1H), 6.06 (s,1H), 7.13 (s, 1H), 7.24-7.27 (m, 2H), 7.34 (d, J = 1.73 Hz, 1H), 12.06(brs, 1H) 24 (400 MHz, DMSO-D6) 0.70-0.72 (m, 3H), 0.90-0.98 449 447 (m,9H), 1.05-1.07 (m, 6H), 1.36-1.40 (m, 2H), 1.47-1.50 (m, 1H), 1.61 (s,3H), 1.76-1.83 (m, 1H), 1.95-2.01 (m, 1H), 2.26-2.31 (m, 1H), 2.60-2.64(m, 2H), 3.23-3.27 (m, 1H), 3.35-3.54 (m, 1H), 6.04 (d, J = 4.39 Hz,1H), 7.02 (d, J = 5.78 Hz, 1H), 7.23-7.32 (m, 2H), 7.34 (d, J = 1.62 Hz,1H), 12.12 (s, 1H) 25 (400 MHz, DMSO-D6) 0.70-0.72 (m, 3H), 0.90-0.98449 447 (m, 9H), 1.05-1.07 (m, 6H), 1.36-1.40 (m, 2H), 1.47-1.50 (m,1H), 1.61 (s, 3H), 1.76-1.83 (m, 1H), 1.95-2.01 (m, 1H), 2.26-2.31 (m,1H), 2.60-2.64 (m, 2H), 3.23-3.27 (m, 1H), 3.35-3.54 (m, 1H), 6.04 (d, J= 4.39 Hz, 1H), 7.02 (d, J = 5.78 Hz, 1H), 7.23-7.32 (m, 2H), 7.34 (d, J= 1.62 Hz, 1H), 12.12 (s, 1H) 26 (400 MHz, CDCl3) δ: 0.70 (t, J = 6.65Hz, 3H), 0.94 401 399 (d, J = 12.89 Hz, 9H), 1.05 (q, J = 3.49 Hz, 3H),1.45-1.50 (m, 2H), 1.72 (d, J = 9.67 Hz, 3H), 1.92 (dd, J = 10.88, 6.85Hz, 3H), 2.37 (t, J = 6.85 Hz, 2H), 2.53-2.57 (m, 2H), 3.55 (q, J = 6.31Hz, 2H), 5.36-5.49 (m, 1H), 5.78 (s, 1H), 7.14 (d, J = 8.46 Hz, 2H),7.31 (dd, J = 8.26, 4.23 Hz, 2H). 27 (400 MHz, CDCl3) δ: 0.71 (dd, J =12.69, 6.65 Hz, 421 419 3H), 0.93 (dd, J = 14.51, 11.69 Hz, 6H), 1.06(dd, J = 20.75, 13.90 Hz, 3H), 1.48 (dt, J = 17.19, 7.45 Hz, 2H), 1.61(td, J = 13.30, 6.85 Hz, 1H), 1.69 (d, J = 14.10 Hz, 3H), 1.87-1.94 (m,3H), 2.38 (t, J = 6.85 Hz, 2H), 2.67-2.71 (m, 2H), 3.55 (dq, J = 25.39,6.58 Hz, 2H), 5.47 (s, 1H), 5.80 (d, J = 11.69 Hz, 1H), 7.17 (d, J =8.06 Hz, 1H), 7.24 (dd, J = 8.06, 2.01 Hz, 1H), 7.37 (d, J = 2.01 Hz,1H). 28 (400 MHz, CDCl3) δ: 0.72 (d, J = 6.85 Hz, 3H), 0.94 407 405 (t,J = 7.25 Hz, 3H), 1.06 (d, J = 6.85 Hz, 3H), 1.37 (t, J = 7.45 Hz, 2H),1.57 (dd, J = 15.51, 7.86 Hz, 2H), 1.72 (s, 3H), 1.93 (dt, J = 18.67,6.95 Hz, 3H), 2.41 (t, J = 6.85 Hz, 2H), 2.71 (t, J = 7.66 Hz, 2H), 3,58(dd, J = 7.66, 5.64 Hz, 2H), 4.97 (s, 1H), 5.81 (s, 1H), 7.19 (d, J =7.66 Hz, 1H), 7.23 (d, J = 2.01 Hz, 1H), 7.38 (d, J = 1.61 Hz, 1H). 29(400 MHz, DMSO-D6) 0.74 (d, J = 6.94 Hz, 3H), 0.94 475 473 (s, 9H), 1.06(d, J = 6.94 Hz, 3H), 1.34-1.43 (m, 4H), 1.54-1.65 (m, 7H), 1.95-2.05(m, 3H), 2.20-2.27 (m, 1H), 2.59-2.64 (m, 2H), 4.03-4.09 (m, 1H), 6.13(s, 1H), 7.01 (s, 1H), 7.24 (dd, J = 8.09, 1.85 Hz, 1H), 7.29 (d, J =8.09 Hz, 1H), 7.33 (d, J = 1.85 Hz, 1H), 12.05 (s, 1H) 30 (400 MHz,DMSO-D6) 0.70 (d, J = 6.94 Hz, 3H), 0.94 475 473 (s, 9H), 1.03 (d, J =6.70 Hz, 3H), 1.24-1.25 (m, 1H), 1.38 (dt, J = 10.33, 3.41 Hz, 2H),1.44-1.60 (m, 9H), 2.02-2.13 (m, 3H), 2.60-2.62 (m, 2H), 4.07-4.09 (m,1H), 5.91 (s, 1H), 7.03 (s, 1H), 7.23 (dd, J = 7.98, 1.97 Hz, 1H), 7.29(d, J = 7.86 Hz, 1H), 7.33 (d, J = 1.85 Hz, 1H) 31 (400 MHz, CDCl3)0.87-0.94 (m, 2H), 0.96 (s, 9H), 475 473 1.02-1.18 (m, 4H), 1.41-1.45(m, 2H), 1.47-1.59 (m, 3H), 1.67 (s, 3H), 1.68-1.79 (m, 2H), 1.87-1.94(m, 2H), 2.35 (t, J = 6.94 Hz, 2H), 2.63-2.68 (m, 2H), 3.52 (t, J = 6.47Hz, 2H), 5.20 (s, 1H), 5.76 (s, 1H), 7.15 (d, J = 8.09 Hz, 1H), 7.21(dd, J = 7.98, 1.97 Hz, 1H), 7.35 (d, J = 1.85 Hz, 1H) 32 (400 MHz,CDCl3) 0.89-0.95 (m, 2H), 0.96 (s, 9H), 475 473 1.04-1.17 (m, 4H),1.41-1.45 (m, 2H), 1.47-1.59 (m, 3H), 1.68 (s, 3H), 1.70-1.79 (m, 2H),1.89-1.96 (m, 2H), 2.38 (t, J = 6.94 Hz, 2H), 2.64-2.68 (m, 2H), 3.55(t, J = 6.59 Hz, 2H), 5.05 (s, 1H), 5.77 (s, 1H), 7.16 (d, J = 8.09 Hz,1H), 7.21 (dd, J = 8.09, 2.08 Hz, 1H), 7.35 (d, J = 2.08 Hz, 1H) 33 (400MHz, DMSO-D6) 0.38 (t, J = 7.34 Hz, 1.5H), 0.61 449 447 (d, J = 6.82 Hz,1.5H), 0.83 (t, J = 7.34 Hz, 1.5H), 0.94 (s, 4.5H), 0.95 (s, 4.5H), 1.02(d, J = 6.70 Hz, 1.5H), 1.04-1.06 (m, 1H), 1.24-1.31 (m, 0.5H), 1.37(dt, J = 12.48, 5.12 Hz, 2H), 1.42-1.49 (m, 0.5H), 1.58 (s, 1.5H), 1.61(s, 1.5H), 1.69-1.71 (m, 3H), 2.17-2.18 (m, 2H), 2.61-2.63 (m, 2H),3.23-3.53 (m, 3H), 5.93 (s, 0.5H), 5.96 (s, 0.5H), 7.00 (s, 0.5H), 7.02(s, 0.5H), 7.26-7.28 (m, 2H), 7.34 (d, J = 1.62 Hz, 0.5H), 7.35 (d, J =1.50 Hz, 0.5H), 12.09 (brs, 1H) 34 (400 MHz, DMSO-D6) 0.38 (t, J = 7.28Hz, 1.5H), 0.61 449 447 (d, J = 6.82 Hz, 1.5H), 0.83 (t, J = 7.34 Hz,1.5H), 0.94 (s, 4.5H), 0.95 (s, 4.5H), 1.02 (d, J = 6.82 Hz, 1.5H),1.05-1.07 (m, 1H), 1.24-1.31 (m, 0.5H), 1.36-1.39 (m, 2H), 1.42-1.49 (m,0.5H), 1.58 (s, 1.5H), 1.61 (s, 1.5H), 1.69-1.72 (m, 3H), 2.17-2.19 (m,2H), 2.61-2.63 (m, 2H), 3.23-3.53 (m, 3H), 5.93 (s, 0.5H), 5.97 (s,0.5H), 7.00 (s, 0.5H), 7.02 (s, 0.5H), 7.26-7.28 (m, 2H), 7.34 (d, J =1.62 Hz, 0.5H), 7.35 (d, J = 1.50 Hz, 0.5H), 12.10 (brs, 1H) 35 (400MHz, DMSO-D6) 0.76 (d, J = 6.82 Hz, 3H), 0.87 463 461 (s, 3H), 0.89 (s,3H), 0.94 (s, 9H), 1.04 (d, J = 6.82 Hz, 3H), 1.35-1.40 (m, 2H), 1.61(s, 3H), 2.02-2.07 (m, 3H), 2.60-2.64 (m, 2H), 3.17 (d, J = 13.99 Hz,1H), 3.56 (d, J = 13.99 Hz, 1H), 6.08 (s, 1H), 7.17 (bs, 1H), 7.29-7.29(m, 2H), 7.39 (s, 1H), 12.09 (bs, 1H) 36 (400 MHz, DMSO-D6) 0.76 (d, J =6.82 Hz, 3H), 0.87 463 461 (s, 3H), 0.89 (s, 3H), 0.94 (s, 9H), 1.04 (d,J = 6.82 Hz, 3H), 1.35-1.40 (m, 2H), 1.61 (s, 3H), 2.02-2.07 (m, 3H),2.60-2.64 (m, 2H), 3.17 (d, J = 13.99 Hz. 1H), 3.56 (d, J = 13.99 Hz,1H), 6.08 (s, 1H), 7.17 (bs, 1H), 7.29-7.29 (m, 2H), 7.39 (s, 1H), 12.09(bs, 1H) 37 (400 MHz, DMSO-D6) 0.72-0.79 (m, 6H), 0.95 (s, 449 447 9H),1.35-1.40 (m, 2H), 1.45-1.50 (m, 1H), 1.55-1.58 (m, 4H), 1.65-1.72 (m,3H), 2.16 (t, J = 7.51 Hz, 2H), 2.60-2.64 (m, 2H), 3.27-3.31 (m, 1H),3.42-3.48 (m, 1H), 5.94 (s, 1H), 7.05 (s, 1H), 7.25-7.28 (m, 2H), 7.35(d, J = 1.73 Hz, 1H), 12.08 (brs, 1H) 38 (400 MHz, DMSO-D6) 0.73-0.76(m, 6H), 0.95 (s, 449 447 9H), 1.35-1.40 (m, 2H), 1.45-1.49 (m, 1H),1.55-1.58 (m, 4H), 1.68-1.70 (m, 3H), 2.16 (t, J = 7.51 Hz, 2H),2.60-2.64 (m, 2H), 3.27-3.30 (m, 1H), 3.41-3.48 (m, 1H), 5.94 (s, 1H),7.05 (s, 1H), 7.25-7.28 (m, 2H), 7.35 (d, J = 1.73 Hz, 1H), 12.08 (brs,1H) 39 (400 MHz, DMSO-D6) 0.69 (d, J = 6.70 Hz, 3H), 0.95 451 449 (s,9H), 1.03 (d, J = 6.70 Hz, 3H), 1.38 (dt, J = 8.79, 3.73 Hz, 2H), 1.61(s, 3H), 1.93-1.96 (m, 1H), 2.62 (dt, J = 10.40, 3.73 Hz, 2H), 3.44-3.62(m, 4H), 3.92 (s, 2H), 6.12 (s, 1H), 7.02 (bs, 1H), 7.27-7.30 (m, 2H),7.34-7.36 (m, 1H) 40 (400 MHz, DMSO-D6) 0.69 (d, J = 6.70 Hz, 3H), 0.95451 449 (s, 9H), 1.03 (d, J = 6.70 Hz, 3H), 1.38 (dt, J = 8.79, 3.73 Hz,2H), 1.61 (s, 3H), 1.93-1.96 (m, 1H), 2.62 (dt, J = 10.40, 3.73 Hz, 2H),3.44-3.62 (m, 4H), 3.92 (s, 2H), 6.12 (s, 1H), 7.02 (bs, 1H), 7.27-7.30(m, 2H), 7.34-7.36 (m, 1H) 41 (400 MHz, DMSO-D6) 0.67-0.79 (m, 3H), 0.94(s, 447 445 9H), 1.03-1.13 (m, 3H), 1.32-1.43 (m, 2H), 1.54-1.61 (m,3H), 1.93-2.05 (m, 1H), 2.14-2.35 (m, 5H), 2.54-2.69 (m, 2H), 4.83-4.99(m, 1H), 6.27 (s, 1H), 6.99 (s, 1H), 7.17-7.35 (m, 3H) 42 (400 MHz,DMSO-D6) 0.67-0.79 (m, 3H), 0.94 (s, 447 445 9H), 1.03-1.13 (m, 3H),1.32-1.43 (m, 2H), 1.54-1.61 (m, 3H), 1.93-2.05 (m, 1H), 2.14-2.35 (m,5H), 2.54-2.69 (m, 2H), 4.83-4.99 (m, 1H), 6.27 (s, 1H), 6.99 (s, 1H),7.17-7.35 (m, 3H) 43 (400 MHz, DMSO-D6) 0.74-0.77 (m, 6H), 0.94 (s, 463461 9H), 1.01-1.10 (m, 1H), 1.14-1.23 (m, 1H), 1.38-1.41 (m, 3H), 1.57(s, 3H), 1.63-1.71 (m, 3H), 1.83-1.90 (m, 1H), 2.14 (t, J = 7.46 Hz,2H), 2.60-2.64 (m, 2H), 3.25-3.27 (m, 1H), 3.40-3.47 (m, 1H), 5.94 (s,1H), 7.05 (s, 1H), 7.24 (dd, J = 7.98, 1.85 Hz, 1H), 7.29 (d, J = 7.98Hz, 1H), 7.34 (d, J = 1.85 Hz, 1H), 12.08 (brs, 1H) 44 (400 MHz,DMSO-D6) 0.74-0.77 (m, 6H), 0.94 (s, 463 461 9H), 1.02-1.06 (m, 1H),1.15-1.21 (m, 1H), 1.38-1.41 (m, 3H), 1.57 (s, 3H), 1.64-1.68 (m, 3H),1.84-1.88 (m, 1H), 2.13 (t, J = 7.46 Hz, 2H), 2.60-2.64 (m, 2H),3.25-3.27 (m, 1H), 3.40-3.47 (m, 1H), 5.94 (s, 1H), 7.05 (s, 1H), 7.24(dd, J = 8.03, 1.79 Hz, 1H), 7.29 (d, J = 8.09 Hz, 1H), 7.34 (d, J =1.85 Hz, 1H) 45 (400 MHz, DMSO-D6) 0.69-0.77 (m, 3H), 0.93 (s, 447 4459H), 1.02-1.10 (m, 3H), 1.30-1.43 (m, 2H), 1.61 (s, 3H), 1.95-2.06 (m,1H), 2.18-2.39 (m, 5H), 2.57-2.65 (m, 2H), 2.66-2.77 (m, 1H), 4.59-4.73(m, 1H), 6.25 (s, 1H), 7.09 (s, 1H), 7.17-7.33 (m, 3H), 12.23 (brs, 1H)46 (400 MHz, DMSO-D6) 0.69-0.77 (m, 3H), 0.93 (s, 447 445 9H), 1.02-1.10(m, 3H), 1.30-1.43 (m, 2H), 1.61 (s, 3H), 1.95-2.06 (m, 1H), 2.18-2.39(m, 5H), 2.57-2.65 (m, 2H), 2.66-2.77 (m, 1H), 4.59-4.73 (m, 1H), 6.25(s, 1H), 7.09 (s, 1H), 7.17-7.33 (m. 3H), 12.23 (brs, 1H) 47 (400 MHz,DMSO-D6) 0.64-0.72 (m, 3H), 0.93 (s, 449 447 9H), 1.00-1.05 (m, 3H),1.31-1.40 (m, 2H), 1.40-1.51 (m, 4H), 1.59 (s, 3H), 1.90-2.00 (m, 1H),2.18-2.25 (m, 2H), 2.55-2.65 (m, 2H), 3.21-3.28 (m, 1H), 3.38-3.46 (m,1H), 6.04 (s, 1H), 6.95 (brs, 1H), 7.21-7.29 (m, 2H), 7.31-7.34 (m, 1H),11.94 (brs, 1H) 48 (400 MHz, DMSO-D6) 0.64-0.72 (m, 3H), 0.93 (s, 449447 9H), 1.00-1.05 (m, 3H), 1.31-1.40 (m, 2H), 1.40-1.51 (m, 4H), 1.59(s, 3H), 1.90-2.00 (m, 1H), 2.18-2.25 (m, 2H), 2.55-2.65 (m, 2H),3.21-3.28 (m, 1H), 3.38-3.46 (m, 1H), 6.04 (s, 1H), 6.95 (brs, 1H),7.21-7.29 (m, 2H), 7.31-7.34 (m, 1H), 11.94 (brs, 1H) 49 (400 MHz,DMSO-D6) 0.47-0.54 (m, 3H), 0.86-0.91 497 495 (m, 3H), 0.94 (s, 9H),1.33-1.42 (m, 2H), 1.54 (s, 3H), 1.75-1.88 (m, 1H), 2.57-2.65 (m, 2H),2.81-2.90 (m, 2H), 3.49-3.59 (m, 1H), 3.70-3.81 (m, 1H), 5.78 (s, 1H),6.96 (s, 1H), 7.09-7.15 (m, 1H), 7.21-7.27 (m, 1H), 7.27-7.34 (m, 3H),7.80-7.86 (m, 2H), 12.75 (brs, 1H) 50 (400 MHz, DMSO-D6) 0.47-0.54 (m,3H), 0.86-0.91 497 495 (m, 3H), 0.94 (s, 9H), 1.33-1.42 (m, 2H), 1.54(s, 3H), 1.75-1.88 (m, 1H), 2.57-2.65 (m, 2H), 2.81-2.90 (m, 2H),3.49-3.59 (m, 1H), 3.70-3.81 (m, 1H), 5.78 (s, 1H), 6.96 (s, 1H),7.09-7.15 (m, 1H), 7.21-7.27 (m, 1H), 7.27-7.34 (m, 3H), 7.80-7.86 (m,2H), 12.75 (brs, 1H) 51 (400 MHz, DMSO-D6) 0.15-0.19 (m, 1H), 0.51-0.41447 445 (m, 3H), 0.79 (s, 3H), 0.94 (s, 9H), 1.36-1.40 (m, 2H),1.66-1.71 (m, 2H), 1.74 (s, 3H), 2.16 (t, J = 7.49 Hz, 2H), 2.60-2.64(m, 2H), 3.16-3.27 (m, 1H), 3.47-3.55 (m, 1H), 6.25 (s, 1H), 7.08 (s,1H), 7.27 (d, J = 0.97 Hz, 2H), 7.38 (s, 1H), 12.05 (brs, 1H) 52 (400MHz, DMSO-D6) 0.16-0.19 (m. 1H), 0.41-0.51 447 445 (m, 3H), 0.79 (s,3H), 0.94 (s, 9H), 1.36-1.40 (m, 2H), 1.66-1.71 (m, 2H), 1.73 (s, 3H),2.19-2.13 (m, 2H), 2.60-2.64 (m, 2H), 3.18-3.25 (m, 1H), 3.47-3.55 (m,1H), 6.25 (s, 1H), 7.08 (s, 1H), 7.27 (s, 2H), 7.38 (s, 1H), 12.04 (brs,1H) 53 (400 MHz, CDCl3) δ: 0.72 (d, J = 6.85 Hz, 3H), 0.90 421 419 (t, J= 6.85 Hz, 3H), 1.06 (d, J = 6.85 Hz, 3H), 1.35 (t, J = 3.63 Hz, 4H),1.60 (t, J = 7.45 Hz, 2H), 1.73 (d, J = 8.06 Hz, 3H), 1.93 (tt, J =17.93, 5.31 Hz, 3H), 2.41 (t, J = 7.05 Hz, 2H), 2.70 (t, J = 7.66 Hz,2H), 3.58 (td, J = 6.55, 3.49 Hz, 2H), 5.06 (s, 1H), 5.82 (s, 1H), 7.18(d, J = 8.06 Hz, 1H), 7.23 (d, J = 2.01 Hz, 1H), 7.38 (d, J = 2.01 Hz,1H). 54 (400 MHz, DMSO-D6) 0.70 (d, J = 6.82 Hz, 3H), 0.95 463 461 (s,9H), 1.04 (d, J = 6.82 Hz, 3H), 1.12 (s, 6H), 1.36-1.40 (m, 2H), 1.60(s, 3H), 1.63-1.68 (m, 2H), 1.97-1.98 (m, 1H), 2.60-2.64 (m, 2H),3.27-3.41 (m, 4H), 6.00 (s, 1H), 7.00 (bs, 1H), 7.26 (dd, J = 8.09, 1.85Hz, 1H), 7.30 (d, J = 8.09 Hz, 1H), 7.34 (d, J = 1.85 Hz, 1H), 12.18(bs, 1H) 55 (400 MHz, DMSO-D6) 0.70 (d, J = 6.82 Hz, 3H), 0.95 463 461(s, 9H), 1.04 (d, J = 6.82 Hz, 3H), 1.12 (s, 6H), 1.36-1.40 (m, 2H),1.60 (s, 3H), 1.63-1.68 (m, 2H), 1.97-1.98 (m, 1H), 2.60-2.64 (m, 2H),3.27-3.41 (m, 4H), 6.00 (s, 1H), 7.00 (bs, 1H), 7.26 (dd, J = 8.09, 1.85Hz, 1H), 7.30 (d, J = 8.09 Hz, 1H), 7.34 (d, J = 1.85 Hz, 1H), 12.18(bs, 1H) 56 (400 MHz, CDCl3) 0.20-0.26 (m, 1H), 0.27-0.32 (m, 433 4311H), 0.38-0.45 (m, 1H), 0.60-0.67 (m, 1H), 0.86-0.92 (m, 1H), 0.98 (s,9H), 1.42-1.47 (m, 2H), 1.80 (s, 3H), 1.89-1.96 (m, 2H), 2.39 (t, J =7.05 Hz, 2H), 2.65-2.69 (m, 2H), 3.54 (ddd, J = 6.85, 6.85, 2.82 Hz,2H), 5.09 (s, 1H), 5.65 (d, J = 1.61 Hz, 1H), 7.19 (d. J = 8.06 Hz, 1H),7.27 (dd, J = 4.43, 2.01 Hz, 1H), 7.41 (d, J = 2.01 Hz, 1H) 57 (400 MHz,CDCl3) 0.20-0.26 (m, 1H), 0.27-0.32 (m, 433 431 1H), 0.38-0.45 (m, 1H),0.60-0.67 (m, 1H), 0.86-0.92 (m, 1H), 0.98 (s, 9H), 1.42-1.47 (m, 2H),1.80 (s, 3H), 1.89-1.96 (m, 2H), 2.39 (t, J = 7.05 Hz, 2H), 2.65-2.69(m, 2H), 3.54 (ddd, J = 6.85, 6.85, 2.82 Hz, 2H), 5.09 (s, 1H), 5.65 (d,J = 1.61 Hz, 1H), 7.19 (d, J = 8.06 Hz, 1H), 7.27 (dd. 3 = 4.43, 2.01Hz, 1H), 7.41 (d, J = 2.01 Hz, 1H) 58 (400 MHz, CDCl3) 0.98 (s, 9H),1.42-1.47 (m, 2H), 447 445 3.52-1.67 (m, 3H), 1.64 (s, 3H), 1.69-1.76(m, 1H), 1.80-1.88 (m, 1H), 1.92-2.03 (m, 3H), 2.40 (t, J = 7.25 Hz,2H), 2.51-2.59 (m, 1H), 2.64-2.68 (m, 2H), 3.57 (ddd, J = 14.91, 12.89,8.06 Hz, 2H), 5.32 (s, 1H), 5.77 (d, J = 1.21 Hz, 1H), 7.16 (d, J = 8.06Hz, 1H), 7.20 (dd, J = 8.06, 2.01 Hz, 1H), 7.34 (d, J = 1.61 Hz, 1H) 59(400 MHz, CDCl3) 0.98 (s, 9H), 1.42-1.47 (m, 2H), 447 445 1.52-1.67 (m,3H), 1.64 (s, 3H), 1.69-1.76 (m, 1H), 1.80-1.88 (m, 1H), 1.92-2.03 (m,3H), 2.40 (t, J = 7.25 Hz, 2H), 2.51-2.59 (m, 1H), 2.64-2.68 (m, 2H),3.57 (ddd, J = 14.91, 12.89, 8.06 Hz, 2H), 5.32 (s, 1H), 5.77 (d, J =1.21 Hz, 1H), 7.16 (d, J = 8.06 Hz, 1H), 7.20 (dd, J = 8.06, 2.01 Hz,1H), 7.34 (d, J = 1.61 Hz, 1H) 60 (400 MHz, CDCl3) 0.98 (s, 9H),1.42-1.45 (m, 2H), 407 405 1.46 (d, J = 1.61 Hz, 3H), 1.70 (s, 3H),1.90-1.97 (m, 2H), 2.40 (t, J = 6.85 Hz, 2H), 2.65-2.69 (m, 2H), 3.55(t, J = 6.85 Hz, 2H), 5.04 (s, 1H), 5.76 (d, J = 1.21 Hz, 1H), 7.21-7.20(m, 2H), 7.36 (d, J = 1.61 Hz, 1H) 61 (400 MHz, CDCl3) 0.98 (s, 9H),1.42-1.45 (m, 2H), 407 405 1.46 (d, J = 1.61 Hz, 3H), 1.70 (s, 3H),1.90-1.97 (m, 2H), 2.40 (t, J = 6.85 Hz, 2H), 2.65-2.69 (m, 2H), 3.55(t, J = 6.85 Hz, 2H), 5.04 (s, 1H), 5.76 (d, J = 1.21 Hz, 1H), 7.21-7.20(m, 2H), 7.36 (d, J = 1.61 Hz, 1H) 62 (400 MHz, DMSO-D6) 1.02 (s, 9H),1.89-2.01 (m, 393 391 3H), 2.14-2.20 (m, 1H), 2.63-2.72 (m, 1H),2.75-2.81 (m, 1H), 3.69 (s, 2H), 4.66 (s, 1H), 5.95 (d, J = 4.35 Hz,1H), 7.01 (s, 1H), 7.08 (d, J = 8.69 Hz, 1H), 7.13 (dd, J = 8.45, 1.93Hz, 1H), 7.25 (d, J = 1.69 Hz, 1H), 8.11 (d, J = 3.38 Hz, 1H) 63 (400MHz, DMSO-D6) 0.68-0.77 (m, 3H), 0.93 (s, 461 459 9H), 1.00-1.08 (m,3H), 1.32-1.40 (m, 2H), 1.59 (s, 3H), 1.66-1.91 (m, 4H), 1.91-2.06 (m,2H), 2.57-2.64 (m, 2H), 2.67-2.79 (m, 1H), 4.63-4.77 (m, 1H), 6.18 (s,1H), 7.02 (s, 1H), 7.19-7.37 (m, 3H), 12.21 (brs, 1H) 64 (400 MHz,DMSO-D6) 0.68-0.77 (m, 3H), 0.93 (s, 461 459 9H), 1.00-1.08 (m, 3H),1.32-1.40 (m, 2H), 1.59 (s, 3H), 1.66-1.91 (m, 4H), 1.91-2.06 (m, 2H),2.57-2.64 (m, 2H), 2.67-2.79 (m, 1H), 4.63-4.77 (m, 1H), 6.18 (s, 1H),7.02 (s, 1H), 7.19-7.37 (m, 3H), 12.21 (brs, 1H) 65 (400 MHz, CDCl3) δ:0.70 (t, J = 7.66 Hz, 3H), 0.98 (d, 415 413 J = 7.25 Hz, 9H), 1.05 (d, J= 6.85 Hz, 3H), 1.28 (d, J = 15.72 Hz, 2H), 1.37-1.42 (m, 2H), 1.72 (d,J = 5.24 Hz, 3H), 1.88-1.98 (m, 3H), 2.29 (s, 3H), 2.41 (t, J = 6.85 Hz,2H), 2.51-2.55 (m, 2H), 3.57 (ddd, J = 14.81, 8.36, 5.94 Hz, 2H), 5.12(s, 1.H), 5.78 (s, 1H), 7.08 (d, J = 7.66 Hz, 1H), 7.16 (d, J = 7.66 Hz,2H). 66 (400 MHz, DMSO-D6) 0.70 (d, J = 6.94 Hz, 3H), 0.94 475 473 (s,9H), 1.03 (d, J = 6.70 Hz, 3H), 1.24-1.25 (m, 1H), 1.38 (dt, J = 10.33,3.41 Hz, 2H), 1.44-1.60 (m, 9H), 2.02-2.13 (m, 3H), 2.60-2.62 (m, 2H),4.07-4,09 (m, 1H), 5.91 (s, 1H), 7.03 (s, 1H), 7.23 (dd, J = 7.98, 1.97Hz, 1H), 7.29 (d, J = 7.86 Hz, 1H), 7.33 (d, J = 1.85 Hz, 1H) 67 (400MHz, DMSO-D6) 0.70 (d, J = 6.94 Hz, 3H), 0.94 475 473 (s, 9H), 1.03 (d,J = 6.70 Hz, 3H), 1.24-1.25 (m, 1H), 1.38 (dt, J = 10.33, 3.41 Hz, 2H),1.44-1.60 (m, 9H), 2.02-2.13 (m, 3H), 2.60-2.62 (m, 2H), 4.07-4.09 (m,1H), 5.91 (s, 1H), 7.03 (s, 1H), 7.23 (dd, J = 7.98, 1.97 Hz, 1H), 7.29(d, J = 7.86 Hz, 1H), 7.33 (d, J = 1.85 Hz, 1H) 68 (400 MHz, CDCl3) 0.93(t, J = 7.25 Hz, 3H), 0.98 (s, 421 419 9H), 1.42-1.47 (m, 2H), 1.59-1.68(m, 1H), 1.69 (s, 3H), 1.91-1.84 (m, 1H), 1.99-1.92 (m, 2H), 2.40 (t, J= 7.05 Hz, 2H), 2.69-2.64 (m, 2H), 3.58 (t, J = 6.45 Hz, 2H), 5.06 (s,1H), 5.71 (t, J = 1.61 Hz, 1H), 7.18 (d, J = 8.06 Hz, 1H), 7.22 (dd, J =7.66, 2.01 Hz, 1H), 7.35 (d, J = 1.61 Hz, 1H) 69 (400 MHz, CDCl3) 0.93(t, J = 7.25 Hz, 3H), 0.98 (s, 421 419 9H), 1.42-1.47 (m, 2H), 1.59-1.68(m, 1H), 1.69 (s, 3H), 1.91-1.84 (m, 1H), 1.99-1.92 (m, 2H), 2.40 (t, J= 7.05 Hz, 2H), 2.69-2.64 (m, 2H), 3.58 (t, J = 6.45 Hz, 2H), 5.06 (s,1H), 5.71 (t, J = 1.61 Hz, 1H), 7.18 (d, J = 8.06 Hz, 1H), 7.22 (dd, J =7.66, 2.01 Hz, 1H), 7.35 (d, J = 1.61 Hz, 1H) 70 (400 MHz, CDCl3) δ:0.72 (d, J = 6.85 Hz, 3H), 0.91 391 389 (q, J = 8.19 Hz, 3H), 1.06 (d, J= 6.85 Hz, 3H), 1.30-1.40 (m, 2H), 1.57 (dt, J = 16.12, 7.05 Hz, 2H),1.72 (d, J = 9.67 Hz, 3H), 1.93 (td, J = 13.00, 6.45 Hz, 3H), 2.39 (t, J= 6.85 Hz, 2H), 2.61 (t, J = 7.66 Hz, 2H), 3.49-3.60 (m, 2H), 5.33 (s,1H), 5.81 (s, 1H), 7.11 (dq, J = 24.48, 6.18 Hz, 3H). 71 (400 MHz,DMSO-D6) 0.61-0.72 (m, 5H), 0.93 (s, 461 459 9H), 0.98-1.04 (m, 5H),1.32-1.40 (m, 2H), 1.59 (s, 3H), 1.61-1.67 (m, 2H), 1.87-1.98 (m, 1H),2.57-2.65 (m, 2H), 3.44-3.58 (m, 2H), 5.93 (s, 1H), 6.95 (s, 1H),7.22-7.31 (m, 2H), 7.31-7.39 (m, 1H), 12.09 (brs, 1H) 72 (400 MHz,DMSO-D6) 0.61-0.72 (m, 5H), 0.93 (s, 461 459 9H), 0.98-1.04 (m, 5H),1.32-1.40 (m, 2H), 1.59 (s, 3H), 1.61-1.67 (m, 2H), 1.87-1.98 (m, 1H),2.57-2.65 (m, 2H), 3.44-3.58 (m, 2H), 5.93 (s, 1H), 6.95 (s, 1H),7.22-7.31 (m, 2H), 7.31-7.39 (m, 1H), 12.09 (brs, 1H) 73 (400 MHz,CDCl3) 0.68-0.75 (m, 3H), 0.95 (s, 9H), 449 447 0.99-1.07 (m, 3H),1.13-1.28 (m, 3H), 1.37-1.48 (m, 2H), 1.65 (s, 3H), 1.72-1.98 (m, 4H),2.19-2.36 (m, 1H), 2.58-2.68 (m, 2H), 4.56 (brs, 1H), 5.82 (s, 1H),7.08-7.22 (m, 2H), 7.32-7.39 (m, 1H) 74 (400 MHz, DMSO-D6) 0.70-0.72 (m,3H), 0.94 (s, 477 475 9H), 0.98 (s, 6H), 1.01-1.09 (m, 3H), 1.26-1.45(m, 6H), 1.59 (s, 3H), 1.91-2.03 (m, 1.H), 2.59-2.66 (m, 2H), 3.14-3.23(m, 1H), 3.36-3.47 (m, 1H), 6.01 (s, 1H), 6.92 (s, 1H), 7.23-7.32 (m,2H), 7.33-7.39 (m, 1H) 75 (400 MHz, DMSO-D6) 0.70-0.72 (m, 3H), 0.94 (s,477 475 9H), 0.98 (s, 6H), 1.01-1.09 (m, 3H), 1.26-1.45 (m, 6H), 1.59(s, 3H), 1.91-2.03 (m, 1H), 2.59-2.66 (m, 2H), 3.14-3.23 (m, 1H),3.36-3.47 (m, 1H), 6.01 (s, 1H), 6.92 (s, 1H), 7.23-7.32 (m, 2H),7.33-7.39 (m, 1H) 76 (400 MHz, DMSO-D6) 0.63-0.72 (m, 3H), 0.93 (s, 459457 9H), 0.98-1.05 (m, 2H), 1.30-1.43 (m, 2H), 1.57 (s, 3H), 1.89-1.99(m, 1H), 2.06 (brs, 6H), 2.57-2.68 (m, 2H), 5.93 (s, 1H), 6.94 (brs,1H), 7.19-7.35 (m, 3H) 77 (400 MHz, DMSO-D6) 0.63-0.72 (m, 3H), 0.93 (s,459 457 9H), 0.98-1.05 (m, 2H), 1.30-1.43 (m, 2H), 1.57 (s, 3H),1.89-1.99 (m, 1H), 2.06 (brs, 6H), 2.57-2.68 (m, 2H), 5.93 (s, 1H), 6.94(brs, 1H), 7.19-7.35 (m, 3H) 78 (400 MHz, DMSO-D6) 0.74 (d, J = 6.94 Hz,3H), 0.94 475 473 (s, 9H), 1.06 (d, J = 6.94 Hz, 3H), 1.34-1.43 (m, 4H),1.54-1.65 (m, 7H), 1.95-2.05 (m, 3H), 2.20-2.27 (m, 1H), 2.59-2.64 (m,2H), 4.03-4.09 (m, 1H), 6.13 (s, 1H), 7.01 (s, 1H), 7.24 (dd, J = 8.09,1.85 Hz, 1H), 7.29 (d, J = 8.09 Hz, 1H), 7.33 (d, J = 1.85 Hz, 1H),12.05 (s, 1H) 79 (400 MHz, DMSO-D6) 0.74 (d, J = 6.94 Hz, 3H), 0.94 475473 (s, 9H), 1.06 (d, J = 6.94 Hz, 3H), 1.34-1.43 (m, 4H), 1.54-1.65 (m,7H), 1.95-2.05 (m, 3H), 2.20-2.27 (m, 1H), 2.59-2.64 (m, 2H), 4.03-4.09(m, 1H), 6.13 (s, 1H), 7.01 (s, 1H), 7.24 (dd, J = 8.09, 1.85 Hz, 1H),7.29 (d, J = 8.09 Hz, 1H), 7.33 (d, J = 1.85 Hz, 1H), 12.05 (s, 1H) 80(400 MHz, DMSO-D6) 0.72 (d, J = 6.82 Hz, 3H), 0.94 461 459 (s, 9H), 1.04(d, J = 6.82 Hz, 3H), 1.37 (dt, J = 8.71, 3.67 Hz, 2H), 1.60 (s, 3H),1.88-2.01 (m, 3H), 2.12-2.15 (m, 2H), 2.62 (dt, J = 10.17, 3.67 Hz, 2H),2.97-3.00 (m, 1H), 3.26-3.28 (m, 1H), 3.62 (dd, J = 13.64, 7.40 Hz, 1H),6.11 (s, 1H), 7.01 (bs, 1H), 7.24 (dd, J = 8.09, 1.85 Hz, 1H), 7.28 (d,J = 8.09 Hz, 1H), 7.32 (d, J = 1.85 Hz, 1H), 12.06 (bs, 1H) 81 (400 MHz,CDCl3) 0.98 (s, 9H), 1.42-1.46 (m, 2H), 526 524 1.64 (s, 3H), 1.93-2.00(m, 2H), 2.40 (t J = 7.25 Hz, 2H), 2.65-2.69 (m, 2H), 2.80 (s, 3H),2.88-2.96 (m, 1H), 3.29 (t, J = 7.25 Hz, 1H), 3.45 (t, J = 7.66 Hz, 1H),3.50-3.57 (m, 1H), 3.63-3.70 (m, 1H), 3.84 (d, J = 7.66 Hz, 2H), 5.57(s, 1H), 6.03 (s, 1H), 7.20 (s, 2H), 7.33 (s, 1H) 82 (400 MHz, DMSO-D6)0.52-0.57 (m, 3H), 0.89-0.92 497 495 (m, 3H), 0.94 (s, 9H), 1.31-1.42(m, 2H), 1.55 (s, 3H), 1.78-1.89 (m, 1H), 2.58-2.64 (m, 2H), 3.05-3.18(m, 2H), 3.50-3.59 (m, 1H), 3.61-3.70 (m, 1H), 5.77 (s, 1H), 6.94 (s,1H), 7.15-7.24 (m, 2H), 7.25-7.34 (m, 3H), 7.36-7.45 (m, 1H), 7.77-7.84(m, 1H), 12.91 (brs, 1H) 83 (400 MHz, DMSO-D6) 0.52-0.57 (m, 3H),0.89-0.92 497 495 (m, 3H), 0.94 (s, 9H), 1.31-1.42 (m, 2H), 1.55 (s,3H), 1.78-1.89 (m, 1H), 2.58-2.64 (m, 2H), 3.05-3.18 (m, 2H), 3.50-3.59(m, 1H), 3.61-3.70 (m, 1H), 5.77 (s, 1H), 6.94 (s, 1H), 7.15-7.24 (m,2H), 7.25-7.34 (m, 3H), 7.36-7.45 (m, 1H), 7.77-7.84 (m, 1H), 12.91(brs, 1H) 84 (400 MHz, DMSO-D6) 0.66 (d, J = 6.94 Hz, 3H), 0.88 373 371(t, J = 7.40 Hz, 3H), 1.03 (d, J = 6.94 Hz, 3H), 1.28 (qt, J = 7.40,7.20 Hz, 2H), 1.53 (tt, J = 7.63, 7.20 Hz, 2H), 1.61 (s, 3H), 1.70 (tt,J = 7.40, 6.80 Hz, 2H), 1.94 (sep, J = 6.94 Hz, 1H), 2.18 (t, J = 7.40Hz, 2H), 2.54 (t, J = 7.63 Hz, 2H), 3.31 (dt, J = 13.60, 6.80 Hz, 1H),3.43 (dt, J = 13.60, 6.80 Hz, 1H), 5.99 (s, 1H), 6.87 (s, 1H), 7.14 (d,J = 8.32 Hz, 2H), 7.29 (d, J = 8.32 Hz, 2H), 12.07 (brs, 1H) 85 (400MHz, CDCl3) δ: 0.61 (d, J = 6.85 Hz, 3H), 479 477 0.92 (t, J = 7.25 Hz,3H), 1.01 (d, J = 6.85 Hz, 3H), 1.36 (d, J = 7.25 Hz, 2H), 1.69 (s, 3H),1.96 (d, J = 6.45 Hz, 3H), 2.42 (t, J = 6.65 Hz, 2H), 2.66 (s, 2H), 3.58(d, J = 6.45 Hz, 2H), 4.82 (s, 1H), 5.08 (d, J = 7.25 Hz, 2H), 5.74 (s,1H), 6.92 (d, J = 6.45 Hz, 2H), 7.11 (d, J = 8.46 Hz, 1H), 7.38 (dt, J =13.70, 5.84 Hz, 5H). 86 (400 MHz, DMSO-D6) 0.66-0.71 (m, 3H), 0.94 (s,421 419 9H), 1.00-1.07 (m, 3H), 1.34-1.43 (m, 2H), 1.60 (s, 3H),1.86-1.99 (m, 1H), 2.38-2.46 (m, 2H), 2.59-2.66 (m, 2H), 3.46-3.56 (m,3H), 3.56-3.66 (m, 1H), 6.11 (s, 1H), 7.01 (s, 1H), 7.23-7.31 (m, 2H),7.32-7.35 (m, 1H), 12.27 (brs, 1H) 87 (400 MHz, DMSO-D6) 0.66-0.71 (m,3H), 0.94 (s, 421 419 9H), 1.00-1.07 (m, 3H), 1.34-1.43 (m, 2H), 1.60(s, 3H), 1.86-1.99 (m, 1H), 2.38-2.46 (m, 2H), 2.59-2.66 (m, 2H),3.46-3.56 (m, 1H), 3.56-3.66 (m, 1H), 6.11 (s, 1H), 7.01 (s, 1H),7.23-7.31 (m, 2H), 7.32-7.35 (m, 1H), 12.27 (brs, 1H) 88 (400 MHz,DMSO-D6) 0.65-0.73 (m, 2H), 0.95 (s, 451 449 9H), 1.00-1.07 (m, 2H),1.34-1.42 (m, 2H), 1.54-1.68 (m, 4H), 1.84-2.01 (m, 2H), 2.59-2.66 (m,2H), 3.40-3.52 (m, 2H), 3.77-3.88 (m, 1H), 6.04 (s, 1H), 7.01 (s, 1H),7.23-7.32 (m, 2H), 7.32-7.37 (m, 1H) 89 (400 MHz, DMSO-D6) 0.65-0.73 (m,2H), 0.95 (s, 451 449 9H), 1.00-1.07 (m, 2H), 1.34-1.42 (m, 2H),1.54-1.68 (m, 4H), 1.84-2.01 (m, 2H), 2.59-2.66 (m, 2H), 3.40-3.52 (m,2H), 3.77-3.88 (m, 1H), 6.04 (s, 1H), 7.01 (s, 1H), 7.23-7.32 (m, 2H),7.32-7.37 (m, 1H) 90 (400 MHz, CDCl3) 0.80 (d, J = 7.25 Hz, 3H), 0.97(s, 449 447 9H), 1.14 (d, J = 7.25 Hz, 3H), 1.42-1.47 (m, 2H), 1.65 (s,3H), 1.84-1.91 (m, 2H), 2.04-1.96 (m, 1H), 2.00 (s, 3H), 2.36 (t, J =6.85 Hz, 2H), 2.68-2.64 (m, 2H), 3.78-3.61 (m, 2H), 5.52 (s, 1H), 7.16(d, J = 8.06 Hz, 1H), 7.24 (dd, J = 8.06, 1.61 Hz, 1H), 7.37 (d, J =1.61 Hz, 1H) 91 (400 MHz, CDCl3) 0.93-1.02 (m, 2H), 0.98 (s, 9H), 477475 1.29-1.39 (m, 1H), 1.42-1.47 (m, 2H), 1.51-1.76 (m, 2H), 1.71 (s,3H), 1.90-1.96 (m, 2H), 2.37 (t, J = 7.25 Hz, 2H), 2.64-2.69 (m, 2H),3.08 (dd, J = 12.09, 11.69 Hz, 1H), 3.29 (dd, J = 11.69, 12.49 Hz, 1H),3.48-3.61 (m, 2H), 3.80 (dd, J = 11.69, 3.63 Hz, 1H), 3.95 (dd, J =11.28, 2.82 Hz, 1H), 5.65 (s, 1H), 5.86 (s, 1H), 7.18 (d, J = 8.06 Hz,1H), 7.24 (dd, J = 8.06, 2.01 Hz, 1H), 7.38 (d, J = 1.61 Hz, 1H) 92 (400MHz, CDCl3) 0.93-1.02 (m, 2H), 0.98 (s, 9H), 477 475 1.29-1.39 (m, 1H),1.42-1.47 (m, 2H), 1.51-1.76 (m, 2H), 1.71 (s, 3H), 1.90-1.96 (m, 2H),2.37 (t, J = 7.25 Hz, 2H), 2.64-2.69 (m, 2H), 3.08 (dd, J = 12.09, 11.69Hz, 1H), 3.29 (dd, J = 11.69, 12.49 Hz, 1H), 3.48-3.61 (m, 2H), 3.80(dd, J = 11.69, 3.63 Hz, 1H), 3.95 (dd, J = 11.28, 2.82 Hz, 1H), 5.65(s, 1H), 5.86 (s, 1H), 7.18 (d, J = 8.06 Hz, 1H), 7.24 (dd, J = 8.06,2.01 Hz, 1H), 7.38 (d, J = 1.61 Hz, 1H) 93 (400 MHz, DMSO-D6) 0.60-0.68(m, 3H), 0.93 (s, 407 405 9H), 0.98-1.02 (m, 3H), 1.31-1.40 (m, 2H),1.63 (s, 3H), 1.85-1.96 (m, 1H), 2.57-2.66 (m, 2H), 3.91-4.02 (m, 1H),4.05-4.15 (m, 1H), 6.06 (s, 1H), 7.05 (s, 1H), 7.22-7.29 (m, 1H),7.31-7.38 (m, 1H), 7.43-7.48 (m, 1H), 12.41-12.73 (m, 1H) 94 (400 MHz,DMSO-D6) 0.60-0.68 (m, 3H), 0.93 (s, 407 405 9H), 0.98-1.02 (m, 3H),1.31-1.40 (m, 2H), 1.63 (s, 3H), 1.85-1.96 (m, 1H), 2.57-2.66 (m, 2H),3.91-4.02 (m, 1H), 4.05-4.15 (m, 1H), 6.06 (s, 1H), 7.05 (s, 1H),7.22-7.29 (m, 1H), 7.31-7.38 (m, 1H), 7.43-7.48 (m, 1H), 12.41-12.73 (m,1H) 95 (400 MHz, DMSO-D6) 0.93 (s, 9H), 1.21-1.23 (m, 495 493 1H),1.34-1.38 (m, 2H), 1.54 (s, 3H), 2.21-2.32 (m, 3H), 2.52-2.63 (m, 7H),2.64-2.66 (m, 1H), 4.92-4.96 (m, 1H), 6.38 (s, 1H), 7.20-7.22 (m, 2H),7.29 (d, J = 8.09 Hz, 1H), 7.31 (d, J = 1.85 Hz, 1H) 96 (400 MHz,DMSO-D6) 0.93 (s, 9H), 1.21-1.23 (m, 495 493 1H), 1.34-1.38 (m, 2H),1.54 (s, 3H), 2.23-2.32 (m, 3H), 2.51-2.66 (m, 7H), 2.84-2.90 (m, 1H),4.90-4.98 (m, 1H), 6.38 (s, 1H), 7.21 (dd, J = 7.98, 1.97 Hz, 1H), 7.23(s, 1H), 7.29 (d, J = 8.09 Hz, 1H), 7.31 (d, J = 1.85 Hz, 1H) 97 (400MHz, DMSO-D6) 0.65-0.69 (m, 3H), 0.86-0.91 447 445 (m, 2H), 0.93 (s,9H), 0.99-1.06 (m, 5H), 1.32-1.40 (m, 2H), 1.59 (s, 3H), 1.91-2.01 (m,1H), 2.57-2.64 (m, 2H), 3.65-3.74 (m, 2H), 6.26 (s, 1H), 7.02 (s, 1H),7.21-7.30 (m, 2H), 7.32-7.36 (m, 1H), 12.38 (brs, 1H) 98 (400 MHz,DMSO-D6) 0.65-0.69 (m, 3H), 0.86-0.91 447 445 (m, 2H), 0.93 (s, 9H),0.99-1.06 (m, 5H), 1.32-1.40 (m, 2H), 1.59 (s, 3H), 1.91-2.01 (m, 1H),2.57-2.64 (m, 2H), 3.65-3.74 (m, 2H), 6.26 (s, 1H), 7.02 (s, 1H),7.21-7.30 (m, 2H), 7.32-7.36 (m, 1H), 12.38 (brs, 1H) 99 (400 MHz,CDCl3) 0.93-1.05 (m, 2H), 0.98 (s, 9H), 489 487 1.35-1.47 (m, 3H),1.56-1.77 (m, 2H), 1.70 (s, 3H), 2.56-2.69 (m, 6H), 3.00-3.05 (m, 1H),3.10 (t, J = 11.69 Hz, 1H), 3.30 (t, J = 11.28 Hz, 1H), 3.81 (d, J =12.09 Hz, 1H), 3.96 (d, J = 11.28 Hz, 1H), 4.99-5.08 (m, 1H), 5.61 (s,1H), 6.06 (s, 1H), 7.18 (d, J = 8.06 Hz, 1H), 7.24 (d, J = 10.07 Hz,1H), 7.37 (s, 1H) 100 (400 MHz, CDCl3) 0.93-1.05 (m, 2H), 0.98 (s, 9H),489 487 1.35-1.47 (m, 3H), 1.56-1.77 (m, 2H), 1.70 (s, 3H), 2.56-2.69(m, 6H), 3.00-3.05 (m, 1H), 3.10 (t, J = 11.69 Hz, 1H), 3.30 (t, J =11.28 Hz, 1H), 3.81 (d, J = 12.09 Hz, 1H), 3.96 (d, J = 11.28 Hz, 1H),4.99-5.08 (m, 1H), 5.61 (s, 1H), 6.06 (s, 1H), 7.18 (d, J = 8.06 Hz,1H), 7.24 (d, J = 10.07 Hz, 1H), 7.37 (s, 1H) 101 (400 MHz, CDCl3) 0.97(s, 9H), 1.01 (s, 9H), 1.41-1.45 447 445 (m, 2H), 2.62-2.69 (m, 6H),3.06-3.13 (m, 1H), 4.77 (d, J = 2.90 Hz, 1H), 4.91-5.00 (m, 1H),5.31-5.36 (m, 1H), 6.27 (s, 1H), 7.02 (dd, J = 7.85, 1.81 Hz, 1H), 7.15(d, J = 7.73 Hz, 1H), 7.17 (d, J = 1.69 Hz, 1H) 102 (400 MHz, CDCl3)0.97 (s, 9H), 1.01 (s, 9H), 1.41-1.45 447 445 (m, 2H), 2.62-2.68 (m,6H), 3.05-3.12 (m, 1H), 4.77 (d, J = 3.14 Hz, 1H), 4.91-5.00 (m, 1H),5.39 (d, J = 2.41 Hz, 1H), 6.27 (s, 1H), 7.02 (dd, J = 7.73, 1.93 Hz,1H), 7.15 (d, J = 7.97 Hz, 1H), 7.17 (d, J = 1.93 Hz, 1H) 103 (400 MHz,DMSO-D6) 0.70-0.77 (m, 3H), 0.93 (s, 465 463 9H), 1.03-1.10 (m, 3H),1.33-1.42 (m, 2H), 1.61 (s, 3H), 1.85-1.95 (m, 1H), 2.17-2.29 (m, 2H),2.36-2.47 (m, 2H), 2.55-2.63 (m, 2H), 2.81-2.89 (m, 1H), 4.88-5.01 (m,1H), 6.26 (s, 1H), 6.98 (s, 1H), 7.11-7.20 (m, 1H), 7.27-7.33 (m, 1H),12.18 (brs, 1H) 104 (400 MHz, DMSO-D6) 0.70-0.77 (m, 3H), 0.93 (s, 465463 9H), 1.03-1.10 (m, 3H), 1.33-1.42 (m, 2H), 1.61 (s, 3H), 1.85-1.95(m, 1H), 2.17-2.29 (m, 2H), 2.36-2.47 (m, 2H), 2.55-2.63 (m, 2H),2.81-2.89 (m, 1H), 4.88-5.01 (m, 1H), 6.26 (s, 1H), 6.98 (s, 1H),7.11-7.20 (m, 1H), 7.27-7.33 (m, 1H), 12.18 (brs, 1H) 105 (400 MHz,DMSO-D6) 0.68 (d, J = 6.45 Hz, 3H), 1.03 429 427 (d, J = 6.45 Hz, 3H),1.61 (s, 3H), 1.66-1.74 (m, 2H), 1.93 (qq, J = 6.45, 6.45 Hz, 1H), 2.18(t, J = 7.45 Hz, 2H), 2.71-2.83 (m, 2H), 3.27-3.34 (m, 1H), 3.39-3.46(m, 1H), 4.18 (t, J = 5.84 Hz, 2H), 6.00 (s, 1H), 6.87 (s, 1H), 6.91 (d,J = 8.87 Hz, 2H), 7.31 (d, J = 8.87 Hz, 2H) 106 (400 MHz, DMSO-D6) 0.63(d, J = 6.85 Hz, 3H), 0.84 373 371 (d, J = 6.45 Hz, 6H), 1.02 (d, J =6.85 Hz, 3H), 1.62 (s, 3H), 1.66-1.74 (m, 2H), 1.80 (tsep, J = 6.45,7.25 Hz, 1H), 1.94 (qq, J = 6.85, 6.85 Hz, 1H), 2.18 (t, J = 7.66 Hz,2H), 2.42 (d, J = 7.25 Hz, 2H), 3.28-3.34 (m, 1H), 3.40-3.47 (m, 1H),5.99 (s, 1H), 6.89 (s, 1H), 7.10 (d, J = 8.46 Hz, 2H), 7.29 (d, J = 8.46Hz, 2H), 12.07 (brs, 1H) 107 (400 Mz, DMSO-D6) 0.76 (d, J = 6.76 Hz,1H), 0.96 (d, 461 459 J = 12.56 Hz, 9H), 1.09 (d, J = 6.76 Hz, 1H),1.35-1.40 (m, 2H), 1.60 (s, 3H), 1.86-1.89 (m, 2H), 2.00-2.03 (m, 1H),2.34-2.43 (m, 5H), 2.61-2.65 (m, 2H), 4.87-4.89 (m, 1H), 6.30 (s, 1H),7.05 (s, 1H), 7.22-7.24 (m, 1H), 7.29-7.31 (m, 2H). 108 (400 Mz,DMSO-D6) 0.76 (d, J = 6.76 Hz, 1H), 0.96 (d, 461 459 J = 12.56 Hz, 9H),1.09 (d, J = 6.76 Hz, 1H), 1.35-1.40 (m, 2H), 1.60 (s, 3H), 1.86-1.89(m, 2H), 2.00-2.03 (m, 1H), 2.34-2.43 (m, 5H), 2.61-2.65 (m, 2H),4.87-4.89 (m, 1H), 6.30 (s, 1H), 7.05 (s, 1H), 7.22-7.24 (m, 1H),7.29-7.31 (m, 2H). 109 (400 MHz, DMSO-D6) 0.70 (d, J = 6.94 Hz, 3H),1.04 433 431 (d, J = 6.70 Hz, 3H), 1.57-1.84 (m, 8H), 1.61 (s, 3H),1.94-2.04 (m, 3H), 2.17 (t, J = 7.51 Hz, 2H), 2.20-2.28 (m, 1H), 2.56(dd, J = 8.79, 6.94 Hz, 2H), 3.27-3.34 (m, 1H), 3.42-3.49 (m, 1H), 6.05(s, 1H), 6.99 (s, 1H), 7.27 (s, 2H), 7.35 (s, 1H), 12.04 (s, 1H) 110(400 MHz, DMSO-D6) 0.71 (d, J = 6.94 Hz, 3H), 1.04 433 431 (d, J = 6.70Hz, 3H), 1.57-1.84 (m, 8H), 3.61 (s, 3H), 1.94-2.05 (m, 3H), 2.37 (t, J= 7.51 Hz, 2H), 2.20-2.26 (m, 1H), 2.56 (dd, J = 8.67, 6.82 Hz, 2H),3.27-3.34 (m, 1H), 3.42-3.49 (m, 1H), 6.05 (s, 1H), 7.00 (s, 1H), 7.27(s, 2H), 7.35 (s, 1H), 12.06 (s, 1H) 111 (400 MHz, DMSO-D6) 0.70-0.78(m, 3H), 0.93 (s, 461 459 9H), 1.02-1.09 (m, 3H), 1.30-1.42 (m, 5H),1.60 (s, 3H), 1.96-2.12 (m, 3H), 2.50-2.54 (m, 2H), 2.58-2.67 (m, 2H),4.78-4.95 (m, 1H), 6.30 (s, 1H), 7.11 (s, 1H), 7.18-7.35 (m, 3H), 12.32(brs, 1H) 112 (400 MHz, DMSO-D6) 0.70-0.78 (m, 3H), 0.93 (s, 461 4599H), 1.02-1.09 (m, 3H), 1.30-1.42 (m, 5H), 1.60 (s, 3H), 1.96-2.12 (m,3H), 2.50-2.54 (m, 2H), 2.58-2.67 (m, 2H), 4.78-4.95 (m, 1H), 6.30 (s,1H), 7.11 (s, 1H), 7.18-7.35 (m, 3H), 12.32 (brs, 1H) 113 (400 MHz,DMSO-D6) 0.64 (d, J = 6.70 Hz, 3H), 1.01 371 369 (d, J = 6.70 Hz, 3H),1.09 (s, 3H), 1.10 (s, 3H), 1.60 (s, 3H), 1.89 (sep, J = 6.70 Hz, 1H),2.45 (t, J = 6.94 Hz, 2H), 2.62-2.67 (m, 4H), 3.52 (dt, J = 14.00, 6.94Hz, 1H), 3.62 (dt, J = 14.00, 6.94 Hz, 1H), 6.03 (s, 1H), 6.86 (s, 1H),7.09 (d, J = 7.86 Hz, 1H), 7.12 (d, J = 7.86 Hz, 1H), 7.19 (s, 1H),12.24 (s, 1H) 114 (400 MHz, DMSO-D6) 0.69 (d, J = 6.85 Hz, 3H), 1.04 409407 (d, J = 6.85 Hz, 3H), 1.31 (t, J = 7.25 Hz, 3H), 1.64 (s, 3H), 1.96(qq, J = 6.85, 6.85 Hz, 1H), 2.45 (dd, J = 6.85, 6.85 Hz, 2H), 3.51 (dt,J = 13.50, 6.85 Hz, 1H), 3.65 (dt, J = 13.50, 6.85 Hz, 1H), 4.32 (q, J =7.25 Hz, 2H), 6.15 (s, 1H), 7.16 (s, 1H), 7.46 (dd, J = 8.06, 2.01 Hz,1H), 7.50 (d, J = 2.01 Hz, 1H), 7.77 (d, J = 8.06 Hz, 1H) 115 (400 MHz,DMSO-D6) 0.71 (d, J = 6.76 Hz, 3H), 0.98 445 443 (s, 6H), 1.03 (d, J =6.76 Hz, 3H), 1.45 (t, J = 6.52 Hz, 2H), 1.61 (s, 3H), 1.92-1.99 (m,3H), 2.21-2.26 (m, 2H), 2.45 (t, J = 7.00 Hz, 2H), 3.49-3.56 (m, 1H),3.58-3.65 (m, 1H), 5.54-5.56 (m, 1H), 6.12 (s, 1H), 7.04 (s, 1H), 7.19(d, J = 7.97 Hz, 1H), 7.29 (dd, J = 7.97, 1.93 Hz, 1H), 7.36 (d, J =1.93 Hz, 1H), 12.25 (brs, 1H) 116 (400 MHz, DMSO-D6) 0.71 (d, J = 7.00Hz, 3H), 0.98 445 443 (s, 6H), 1.03 (d, J = 6.76 Hz, 3H), 1.46 (t, J =6.52 Hz, 2H), 1.61 (s, 3H), 1.92-1.99 (m, 3H), 2.22-2.26 (m, 2H), 2.45(t, J = 7.00 Hz, 2H), 3.49-3.56 (m, 1H), 3.59-3.66 (m, 1H), 5.54-5.56(m, 1H), 6.13 (s, 1H), 7.04 (s, 1H), 7.19 (d, J = 7.97 Hz, 1H), 7.29(dd, J = 8.09, 1.81 Hz, 1H), 7.36 (d, J = 1.93 Hz, 1H), 12.26 (brs, 1H)117 (400 MHz, DMSO-D6) 0.69 (d, J = 6.76 Hz, 3H), 0.94 447 445 (s, 3H),0.97 (s, 3H), 1.03 (d, J = 7.00 Hz, 3H), 1.29-1.37 (m, 2H), 1.42-1.49(m, 2H), 1.55-1.60 (m, 7H), 1.90-1.97 (m, 1H), 2.45 (t, J = 7.00 Hz,3H), 2.76-2.84 (m, 1H), 3.48-3.55 (m, 1H), 3.58-3.65 (m, 1H), 6.11 (s,1H), 7.02 (s, 1H), 7.30 (dd, J = 7.97, 1.93 Hz, 1H), 7.34 (d, J = 1.93Hz, 1H), 7.39 (d, J = 8.21 Hz, 1H), 12.26 (brs, 1H) 118 (400 MHz,DMSO-D6) 0.69 (d, J = 7.00 Hz, 3H), 0.94 447 445 (s, 3H), 0.97 (s, 3H),1.03 (d, J = 5.80 Hz, 3H), 1.29-1.37 (m, 2H), 1.45-1.48 (m, 2H),1.55-1.58 (m, 4H), 1.60 (s, 3H), 1.90-1.97 (m, 1H), 2.45 (t, J = 7.00Hz, 2H), 2.76-2.84 (m, 1H), 3.48-3.55 (m, 1H), 3.58-3.65 (m, 1H), 6.11(s, 1H), 7.02 (s, 1H), 7.30 (dd, J = 8.09, 1.81 Hz, 1H), 7.34 (d, J =1.93 Hz, 1H), 7.39 (d, J = 8.21 Hz, 1H), 12.26 (brs, 1H) 119 (400 MHz,DMSO-D6) 0.68 (d, J = 6.94 Hz, 3H), 1.03 433 431 (d, J = 6.70 Hz, 3H),1.07-1.19 (m, 2H), 1.42-1.60 (m, 6H), 1.61 (s, 3H), 1.71-1.81 (m, 3H),1.93 (t, J = 6.70 Hz, 1H), 2.45 (t, J = 6.94 Hz, 2H), 2.65-2.69 (m, 2H),3.54 (dd, J = 13.76, 6.82 Hz, 1H), 3.62 (dd, J = 13.76, 6.82 Hz, 1H),6.11 (s, 1H), 7.02 (s, 1H), 7.27 (dd, J = 7.98, 1.73 Hz, 1H), 7.30 (d, J= 8.09 Hz, 1H), 7.35 (d, J = 1.62 Hz, 1H), 12.30 (s, 1H) 120 (400 MHz,DMSO-D6) 0.68 (d, J = 6.94 Hz, 3H), 1.02 433 431 (d, J = 6.70 Hz, 3H),1.06-1.19 (m, 2H), 1.46-1.58 (m, 6H), 1.60 (s, 3H), 1.70-1.80 (m, 3H),1.89-1.96 (m, 1H), 2.44 (t J = 7.05 Hz, 2H), 2.64-2.68 (m, 2H),3.48-3.55 (m, 1H), 3.58-3.65 (m, 1H), 6.10 (s, 1H), 7.01 (s, 1H), 7.26(dd. J = 8.09, 1.85 Hz, 1H), 7.29 (d, J = 8.09 Hz, 1H), 7.34 (d, J =1.62 Hz, 1H), 12.33 (s, 1H) 121 (400 MHz, DMSO-D6) 0.69 (d, J = 6.94 Hz,3H), 1.03 419 417 (d, J = 6.94 Hz, 3H), 1.57-1.66 (m, 4H), 1.60 (s, 3H),1.75-1.82 (m, 2H), 1.90-1.97 (m, 1H), 1.97-2.05 (m, 2H), 2.24 (t, J =7.74 Hz, 1H), 2.30-2.36 (m, 2H), 2.56 (t, J = 7.86 Hz, 2H), 3.45-3.54(m, 1H), 3.55-3.64 (m, 1H), 6.11 (s, 1H), 6.97 (s, 1H), 7.26 (d, J =0.92 Hz, 2H), 7.33 (s, 1H), 12.44 (s, 1H) 122 (400 MHz, DMSO-D6) 0.69(d, J = 6.94 Hz, 3H), 1.03 419 417 (d, J = 6.70 Hz, 3H), 1.57-1.66 (m,4H), 1.60 (s, 3H), 1.79 (dt, J = 12.02, 5.20 Hz, 2H), 1.94 (dd, J =12.72, 5.55 Hz, 1H), 1.98-2.02 (m, 2H), 2.24 (t, J = 7.74 Hz, 1H),2.29-2.36 (m, 2H), 2.56 (dd, J = 12.95, 4.86 Hz, 2H), 3.45-3.54 (m, 1H),3.55-3.64 (m, 1H), 6.11 (s, 1H), 6.96 (s, 1H), 7.26 (d, J = 0.92 Hz,2H), 7.33 (s, 1H), 12.35 (s, 1H) 123 (400 MHz, DMSO-D6) 0.67 (d, J =6.94 Hz, 3H), 0.84 435 433 (s, 9H), 1.02 (d, J = 6.70 Hz, 3H), 1.17-1.23(m, 2H), 1.47-1.55 (m, 2H), 1.60 (s, 3H), 1.93 (t, J = 7.05 Hz, 1H),2.35-2.44 (m, 2H), 2.63 (t, J = 7.74 Hz, 2H), 3.52 (dd, J = 14.10, 6.94Hz, 1H), 3,60 (dd, J = 14.10, 6.94 Hz, 1H), 6.10 (s, 1H), 7.00 (s, 1H),7.26 (dd, J = 7.60, 1.40 Hz, 1H), 7.29 (d, J = 7.60 Hz, 1H), 7.35 (d, J= 1.39 Hz, 1H), 12.40 (s, 1H) 124 (400 MHz, DMSO-D6) 0.67 (d, J = 6.70Hz, 3H), 0.84 435 433 (s, 9H), 1.02 (d, J = 6.94 Hz, 3H), 1.20 (dd, J =11.10, 5.78 Hz, 2H), 1.47-1.55 (m, 2H), 1.60 (s, 3H), 1.92 (dd, J =11.79, 4.86 Hz, 1H), 2.43 (t, J = 7.05 Hz, 2H), 2.63 (t, J = 7.63 Hz,2H), 3.51 (dd, J = 13.87, 6.94 Hz, 1H), 3.61 (dd, J = 13.87, 6.94 Hz,1H), 6.10 (s, 1H), 7.02 (s, 1H), 7.27 (dd, J = 8.09, 1.62 Hz, 1H), 7.29(d, J = 8.09 Hz, 1H), 7.35 (d. J = 1.39 Hz, 1H), 12.39 (s, 1H) 125 (400MHz, CDCl3) 0.67-0.73 (m, 3H), 1.00 (s, 9H), 437 435 1.02-1.06 (m, 3H),1.69 (s, 3H), 1.75-1.81 (m, 2H), 1.82-1.91 (m, 1H), 2.61-2.68 (m, 2H),3.70-3.84 (m, 2H), 4.04-4.11 (m, 2H), 5.45 (s, 1H), 5.85 (s, 1H),6.83-6.91 (m, 1H), 7.27-7.30 (m, 1H), 7.41-7.43 (m, 1H) 126 (400 MHz,CDCl3) 0.68-0.74 (m, 3H), 1.01-1.06 423 421 (m, 3H), 1.08 (s, 9H), 1.69(s, 3H), 1.82-1.90 (m, 1H), 2.63-2.71 (m, 2H), 3.64 (s, 2H), 3.71-3.82(m, 2H), 5.24 (s, 1H), 5.86 (s, 1H), 6.81-6.87 (m, 1H), 7.22-7.28 (m,1H), 7.39-7.44 (m, 1H) 127 (400 MHz, CDCl3) 0.65-0.73 (m, 3H), 1.00-1.06411 409 (m, 3H), 1.68 (s, 3H), 1.80-1.90 (m, 1H), 2.59-2.69 (m, 2H),3.47 (s, 3H), 3.72-3.78 (m, 2H), 3.78-3.83 (m, 2H), 4.13-4.20 (m, 2H),5.32-5.52 (m, 1H), 5.84 (s, 1H), 6.87-6.92 (m, 1H), 7.26-7.30 (m, 1H),7.40-7.44 (m, 1H) 128 (400 MHz, DMSO-D6) 0.67 (d, J = 6.85 Hz, 3H), 1.02447 445 (d, J = 6.85 Hz, 3H), 1.61 (s, 3H), 1.72-1.80 (m, 2H), 1.93 (qq,J = 6.85, 6.85 Hz, 1H), 2.22-2.35 (m, 2H), 2.44 (dd, J = 6.85, 6.85 Hz,2H), 2.76 (t, J = 7.86 Hz, 2H), 3.52 (dt, J = 13.50, 6.85 Hz, 1H), 3.62(dt, J = 13.50, 6.85 Hz, 1H), 6.11 (s, 1H), 7.03 (s, 1H), 7.30 (dd, J =8.06, 1.61 Hz, 1H), 7.33 (d, J = 8.06 Hz, 1H), 7.38 (d, J = 1.61 Hz, 1H)129 (400 MHz, DMSO-D6) 0.67 (d, J = 6.85 Hz, 3H), 1.02 447 445 (d, J =6.85 Hz, 3H), 1.61 (s, 3H), 1.72-1.80 (m, 2H), 1.93 (qq, J = 6.85, 6.85Hz, 1H), 2.22-2.35 (m, 2H), 2.44 (dd, J = 6.85, 6.85 Hz, 2H), 2.76 (t, J= 7.86 Hz, 2H), 3.52 (dt, J = 13.50, 6.85 Hz, 1H), 3.62 (dt, J = 13.50,6.85 Hz, 1H), 6.11 (s, 1H), 7.04 (s, 1H), 7.30 (dd, J = 8.06, 1.61 Hz,1H), 7.33 (d, J = 8.06 Hz, 1H), 7.38 (d, J = 1.61 Hz, 1H) 130 (400 MHz,DMSO-D6) 0.73 (s, 3H), 0.92 (s, 3H), 0.95 421 419 (s, 9H), 1.27-1.35 (m,1H), 1.36-1.41 (m, 2H), 1.66-1.72 (m, 1H), 1.74 (s, 3H), 1.98-2.13 (m,2H), 2.59-2.64 (m, 2H), 6.00 (d, J = 5.24 Hz, 1H), 6.77 (d, J = 2.01 Hz,1H), 7.28 (s, 2H), 7.36 (s, 1H), 8.22 (dd J = 5.24, 2.42 Hz, 1H), 11.96(br s, 1H) 131 (400 MHz, CDCl3) 0.24-0.30 (m, 4H), 0.71 (d, 419 417 J =6.76 Hz, 3H), 1.05 (d, J = 6.76 Hz, 3H), 1.12 (s, 3H), 1.47-1.51 (m,2H), 1.71 (s, 3H), 1.85-1.92 (m, 1H), 2.69 (t, J = 6.40 Hz, 2H),2.76-2.80 (m, 2H), 3.77 (t, J = 6.52 Hz, 2H), 5.89 (s, 1H), 6.00 (brs,1H), 7.17 (d, J = 8.21 Hz, 1H), 7.23 (dd, J = 7.97, 1.93 Hz, 1H), 7.35(d, J = 1.93 Hz, 1H) 132 (400 MHz, CDCl3) 0.24-0.29 (m, 4H), 0.72 (d,419 417 J = 7.00 Hz, 3H), 1.05 (d, J = 7.00 Hz, 3H), 1.12 (s, 3H),1.47-1.52 (m, 2H), 1.72 (s, 3H), 1.86-1.93 (m, 1H), 2.70 (t, J = 6.40Hz, 2H), 2.76-2.80 (m, 2H), 3.77 (t, J = 6.52 Hz, 2H), 5.90 (s, 1H),6.31 (brs, 1H), 7.18 (d, J = 7.97 Hz, 1H), 7.22 (dd, J = 7.97, 1.93 Hz,1H), 7.34 (d, J = 1.93 Hz, 1H) 133 (400 MHz, DMSO-D6) 0.71 (d, J = 6.76Hz, 3H), 1.03 417 415 (d, J = 6.76 Hz, 3H), 1.60-1.65 (m, 5H), 1.67-1.73(m, 2H), 1.92-1.99 (m, 1H), 2.11-2.16 (m, 2H), 2.20-2.24 (m, 2H), 2.45(t, J = 6.88 Hz, 3H), 3.48-3.56 (m, 1H), 3.58-3.65 (m, 1H), 5.62-5.65(m, 1H), 6.12 (s, 1H), 7.04 (s, 1H), 7.18 (d, J = 8.21 Hz, 1H), 7.29(dd, J = 7.97, 1.93 Hz, 1H), 7.36 (d, J = 1.93 Hz, 1H), 12.26 (brs, 1H)134 (400 MHz, DMSO-D6) 0.71 (d, J = 6.76 Hz, 3H), 1.03 417 415 (d, J =6.76 Hz, 3H), 1.61-1.65 (m, 5H), 1.67-1.73 (m, 2H), 1.92-1.99 (m, 1H),2.12-2.16 (m, 2H), 2.20-2.24 (m, 2H), 2.45 (t, J = 6.88 Hz, 2H),3.49-3.56 (m, 1H), 3.58-3.65 (m, 1H), 5.62-5.64 (m, 1H), 6.12 (s, 1H),7.04 (s, 1H), 7.18 (d, J = 7.97 Hz, 1H), 7.29 (dd, J = 8.09, 1.81 Hz,1H), 7.36 (d, J = 1.93 Hz, 1H), 12.26 (brs, 1H) 135 (400 MHz, DMSO-D6)0.69 (d, J = 7.00 Hz, 3H), 1.02 419 417 (d, J = 6.76 Hz, 3H), 1.19-1.44(m, 5H), 1.60 (s, 3H), 1.70-1.81 (m, 5H), 1.90-1.97 (m, 1H), 2.45 (t J =7.00 Hz, 3H), 2.85-2.91 (m, 1H), 3.48-3.55 (m, 1H), 3.58-3.65 (m, 1H),6.11 (s, 1H), 7.01 (s, 1H), 7.31-7.32 (m, 2H), 7.34 (d, J = 1.69 Hz,1H), 12.26 (brs, 1H) 136 (400 MHz, DMSO-D6) 0.69 (d, J = 6.76 Hz, 3H),1.02 419 417 (d, J = 6.76 Hz, 3H), 1.18-1.44 (m, 5H), 1.60 (s, 3H),1.70-1.81 (m, 5H), 1.90-1.97 (m, 1H), 2.45 (t, J = 6.88 Hz, 2H),2.85-2.91 (m, 1H), 3.48-3.55 (m, 1H), 3.58-3.65 (m, 1H), 6.11 (s, 1H),7.01 (s, 1H), 7.31-7.32 (m, 2H), 7.34 (d, J = 1.45 Hz, 1H), 12.26 (brs,1H) 137 (400 MHz, DMSO-D6) 0.72 (d, J = 6.28 Hz, 3H), 0.76 435 433 (d, J= 6.28 Hz, 3H), 0.95 (s, 9H), 1.36-1.40 (m, 2H), 1.42-1.52 (m, 2H), 1.55(s, 3H), 1.62-1.68 (m, 1H), 2.44 (t, J = 6.76 Hz, 2H), 2.60-2.64 (m,2H), 3.48-3.55 (m, 1H), 3.58-3.64 (m, 1H), 5.99 (s, 1H), 7.06 (s, 1H),7.25 (dd, J = 7.97, 1.69 Hz, 1H), 7.28 (d, J = 7.97 Hz, 1H), 7.33 (d, J= 1.69 Hz, 1H) 138 (400 MHz, DMSO-D6) 0.67 (d, J = 6.76 Hz, 3H),0.86-0.96 447 445 (m, 2H), 1.02-1.04 (m, 4H), 1.16-1.21 (m, 4H),1.40-1.43 (m, 2H), 1.60 (s, 3H), 1.66-1.74 (m, 4H), 1.89-1.96 (m, 1H),2.45 (t, J = 6.88 Hz, 2H), 2.64-2.68 (m, 2H), 3.48-3.65 (m, 2H), 6.10(s, 1H), 7.02 (s, 1H), 7.26-7.27 (m, 2H), 7.34 (s, 1H), 12.30 (br s,1H). 139 (400 MHz, DMSO-D6) 0.67 (d, J = 6.76 Hz, 3H), 0.86-0.96 447 445(m, 2H), 1.02-1.04 (m, 4H), 1.16-1.21 (m, 4H), 1.40-1.43 (m, 2H), 1.60(s, 3H), 1.66-1.74 (m, 4H), 1.89-1.96 (m, 1H), 2.45 (t, J = 6.88 Hz,2H), 2.64-2.68 (m, 2H), 3.48-3.65 (m, 2H), 6.10 (s, 1H), 7.02 (s, 1H),7.26-7.27 (m, 2H), 7.34 (s, 1H), 12.30 (br s, 1H). 140 (400 MHz,DMSO-D6) 0.70 (d, J = 6.85 Hz, 3H), 1.02 449 447 (d, J = 6.85 Hz, 3H),1.60 (s, 3H), 1.92 (qq, J = 6.85, 6.85 Hz, 1H), 2.45 (dd, J = 6.85, 6.85Hz, 2H), 2.76-2.87 (m, 2H), 3.52 (dt, J = 13.50, 6.85 Hz, 1H), 3.63 (dt,J = 13.50, 6.85 Hz, 1H), 4.27 (t, J = 5.84 Hz, 2H), 6.10 (s, 1H), 7.01(s, 1H), 7.14 (d, J = 8.46 Hz, 1H), 7.29 (dd, J = 8.46, 2.42 Hz, 1H),7.38 (d, J = 2.42 Hz, 1H) 141 (400 MHz, DMSO-D6) 0.67 (d, J = 6.94 Hz,3H), 1.01 447 445 (s, 3H), 1.02 (d, J = 6.01 Hz, 3H), 1.09 (s, 3H), 1.38(dd, J = 11.68, 8.67 Hz, 2H), 1.57-1.65 (m, 2H), 1.60 (s, 3H), 1.81 (td,J = 8.84, 2.77 Hz, 2H), 1.92 (dd, J = 8.90, 4.51 Hz, 1H), 2.16 (t, J =8.09 Hz, 1H), 2.45 (t, J = 6.94 Hz, 2H), 2.56 (t, J = 7.74 Hz, 2H), 3.53(dd, J = 13.76, 6.82 Hz, 1H), 3.61 (dd, J = 13.76, 6.82 Hz, 1H), 6.10(s, 1H), 7.02 (s, 1H), 7.26 (d, J = 1.16 Hz, 2H), 7.34 (s, 1H), 12.25(s, 1H) 142 (400 MHz, DMSO-D6) 0.67 (d, J = 6.94 Hz, 3H), 1.01 447 445(s, 3H), 1.02 (d, J = 5.78 Hz, 3H), 1.09 (s, 3H), 1.38 (dd, J = 11.44,8.90 Hz, 2H), 1.57-1.65 (m, 2H), 1.60 (s, 3H), 1.81 (dt, J = 13.18, 4.16Hz, 2H), 1.92 (dd, J = 9.02, 4.62 Hz, 1H), 2.16 (t, J = 8.21 Hz, 1H),2.45 (dd, J = 9.02, 5.09 Hz, 2H), 2.56 (dd, J = 10.06, 5.43 Hz, 2H),3.53 (q, J = 6.86 Hz, 1H), 3.61 (dd, J = 13.76, 6.82 Hz, 1H), 6.10 (s,1H), 7.02 (s, 1H), 7.26 (d, J = 1.16 Hz, 2H), 7.34 (s, 1H), 12.25 (s,1H) 143 (400 MHz, DMSO-D6) 0.69 (d, J = 6.94 Hz, 3H), 1.04 441 439 (d, J= 6.70 Hz, 3H), 1.61 (s, 3H), 1.93 (dd, J = 11.10, 4.39 Hz, 1H), 2.45(dd, J = 9.83, 4.28 Hz, 2H), 2.85 (dd, J = 9.83, 5.90 Hz, 2H), 2.96 (dd,J = 9.71, 5.55 Hz, 2H), 3.53 (t, J = 6.82 Hz, 1H), 3.63 (t, J = 6.94 Hz,1H), 6.11 (s, 1H), 7.03 (s, 1H). 7.17-7.23 (m, 3H), 7.26-7.29 (m, 4H),7.38 (d, J = 1.39 Hz, 1H), 12.30 (s, 1H) 144 (400 MHz, DMSO-D6) 0.69 (d,J = 6.70 Hz, 3H), 1.03 441 439 (d, J = 6.94 Hz, 3H), 1.60 (s, 3H),1.90-1.97 (m, 1H), 2.29-2.35 (m, 2H), 2.84 (dd, J = 9.71, 5.55 Hz, 2H),2.94 (dd, J = 9.59, 5.43 Hz, 2H), 3.53 (t, J = 6.82 Hz, 1H), 3.63 (t, J= 6.94 Hz, 1H), 6.11 (s, 1H), 6.98 (s, 1H), 7.16-7.21 (m, 3H), 7.23-7.29(m, 4H), 7.37 (d, J = 1.62 Hz, 1H), 12.50 (s, 1H) 145 (400 MHz, CDCl3)0.98 (s, 9H), 1.42-1.47 (m, 2H), 483 481 1.68 (s, 3H), 1.93-2.07 (m,3H), 2.08-2.18 (m, 1H), 2.32-2.46 (m, 4H), 2.60-2.69 (m, 3H), 3.67-3.53(m, 2H), 5.20 (s, 1H), 5.85 (d, J = 1.21 Hz, 1H), 7.20 (s, 2H), 7.36 (s,1H) 146 (400 MHz, CDCl3) 0.98 (s, 9H), 1.42-1.47 (m, 2H), 483 481 1.68(s, 3H), 1.93-2.07 (m, 3H), 2.08-2.18 (m, 1H), 2.32-2.46 (m, 4H),2.60-2.69 (m, 3H), 3.67-3.53 (m, 2H), 5.20 (s, 1H), 5.85 (d, J = 1.21Hz, 1H), 7.20 (s, 2H), 7.36 (s, 1H) 147 (400 MHz, DMSO-D6) 0.64-0.71 (m,3H), 0.99-1.04 423 421 (m, 3H), 1.22 (s, 9H), 1.59 (s, 3H), 1.87-1.96(m, 1H), 2.40-2.46 (m, 2H), 3.42-3.56 (m, 1H), 3.56-3.69 (m, 1H), 4.42(s, 2H), 6.09 (s, 1H), 7.02 (s, 1H), 7.27-7.38 (m, 2H), 7.40-7.49 (m,1H), 12.24 (brs, 1H) 148 (400 MHz, DMSO-D6) 0.72 (d, J = 6.70 Hz, 3H),1.04 403 401 (d, J = 6.70 Hz, 3H), 1.61 (s, 3H), 1.90-1.98 (m, 3H),2.42-2.53 (m, 4H), 2.67-2.72 (m, 2H), 3.48-3.55 (m, 1H), 3.62 (dd, J =13.87, 6.94 Hz, 1H), 6.13 (s, 1H), 6.14-6.16 (m, 1H), 7.05 (s, 1H), 7.30(dd, J = 8.21, 1.73 Hz, 1H), 7.33 (d, J = 7.86 Hz, 1H), 7.38 (d, J =1.62 Hz, 1H), 12.26 (s, 1H) 149 (400 MHz, DMSO-D6) 0.72 (d, J = 6.94 Hz,3H), 1.03 403 401 (d, J = 6.70 Hz, 3H), 1.61 (s, 3H), 1.95 (dt, J =20.88, 6.59 Hz, 3H), 2.42-2.51 (m, 4H), 2.69 (td, J = 7.51, 2.00 Hz,2H), 3.48-3.55 (m, 1H), 3.59-3.66 (m, 1H), 6.13 (s, 1H), 6.15 (dd, J =4.16, 2.31 Hz, 1H), 7.05 (s, 1H), 7.30 (dd, J = 8.21, 1.73 Hz, 1H), 7.33(d, J = 8.09 Hz, 1H), 7.38 (d, J = 1.62 Hz, 1H), 12.31 (s, 1H) 150 (400MHz, DMSO-D6) 0.69 (d, J = 6.85 Hz, 3H), 0.93 423 421 (d, J = 6.45 Hz,6H), 1.02 (d, J = 6.85 Hz, 3H), 1.59 (s, 3H), 1.63 (dt, J = 6.65, 6.70Hz, 2H), 1.81 (tsep, J = 6.70, 6.45 Hz, 1H), 1.92 (qq, J = 6.85, 6.85Hz, 1H), 2.44 (dd, J = 7.05, 7.05 Hz, 2H), 3.51 (dt, J = 13.50, 7.05 Hz,1H), 3.62 (dt, J = 13.50, 7.05 Hz, 1H), 4.06 (t, J = 6.65 Hz, 2H), 6.09(s, 1H), 6.98 (s, 1H), 7.10 (d, J = 8.87 Hz, 1H), 7.27 (dd, J = 8.87,2.42 Hz, 1H), 7.35 (d, J = 2.42 Hz, 1H) 151 (400 MHz, DMSO-D6) 0.71 (d,J = 6.76 Hz, 3H), 1.03 445 443 (s, 6H), 1.03 (d, J = 6.76 Hz, 3H),1.46-1.49 (m, 2H), 1.61 (s, 3H), 1.68-1.74 (m, 2H), 1.91-1.98 (m, 1H),2.16 (t, J = 5.92 Hz, 2H), 2.45 (t, J = 6.88 Hz, 2H), 3.48-3.55 (m, 1H),3.59-3.66 (m, 1H), 5.37 (s, 1H), 6.12 (s, 1H), 7.04 (s, 1H), 7.16 (d, J= 7.97 Hz, 1H), 7.29 (dd, J = 7.97, 1.45 Hz, 1H), 7.36 (d, J = 1.21 Hz,1H), 12.24 (brs, 1H) 152 (400 MHz, DMSO-D6) 0.69 (d, J = 7.00 Hz, 3H),1.03 391 389 (d, J = 6.76 Hz, 3H), 1.61 (s, 3H), 1.75-1.82 (m, 1H),1.90-2.10 (m, 4H), 2.30-2.37 (m, 2H), 2.45 (t, J = 7.00 Hz, 2H),3.48-3.55 (m, 1H), 3.59-3.74 (m, 2H), 6.11 (s, 1H), 7.02 (s, 1H),7.31-7.33 (m, 2H), 7.37 (d, J = 8.93 Hz, 1H), 12.26 (brs, 1H) 153 (400MHz, DMSO-D6) 0.69 (d, J = 7.00 Hz, 3H), 1.03 391 389 (d, J = 6.76 Hz,3H), 1.60 (s, 3H), 1.75-1.82 (m, 1H), 1.90-2.10 (m, 4H), 2.30-2.36 (m,2H), 2.45 (t, J = 7.00 Hz, 2H), 3.48-3.55 (m, 1H), 3.59-3.74 (m, 2H),6.11 (s, 1H), 7.02 (s, 1H), 7.32 (dd, J = 7.49, 1.69 Hz, 1H), 7.33 (s,1H), 7.37 (d, J = 8.69 Hz, 1H), 12.25 (brs, 1H) 154 (400 MHz, DMSO-D6)0.72 (d, J = 6.82 Hz, 3H), 0.94 461 459 (s, 9H), 1.04 (d, J = 6.82 Hz,3H), 1.37 (dt, J = 8.71, 3.67 Hz, 2H), 1.60 (s, 3H), 1.88-2.01 (m, 3H),2.12-2.15 (m, 2H), 2.62 (dt, J = 10.17, 3.67 Hz, 2H), 2.97-3.00 (m, 1H),3.26-3.28 (m, 1H), 3.62 (dd, J = 13.64, 7.40 Hz, 1H), 6.11 (s, 1H), 7.01(bs, 1H), 7.24 (dd, J = 8.09, 1.85 Hz, 1H), 7.28 (d, J = 8.09 Hz, 1H),7.32 (d, J = 1.85 Hz, 1H), 12.06 (bs, 1H) 155 (400 MHz, DMSO-D6) 0.70(d, J = 6.94 Hz, 3H), 1.03 405 403 (d, J = 6.70 Hz, 3H), 1.50-1.57 (m,2H), 1.61 (s, 3H), 1.61-1.70 (m, 2H), 1.72-1.81 (m, 2H), 1.90-2.02 (m,3H), 2.44 (t, J = 6.94 Hz, 2H), 3.28-3.34 (m, 1H), 3.52 (q, J = 7.01 Hz,1H), 3.61 (dd, J = 13.87, 6.94 Hz, 1H), 6.11 (s, 1H), 7.01 (s, 1H), 7.29(dd, J = 8.21, 1.97 Hz, 1H), 7.35 (d, J = 1.95 Hz, 1H), 7.35 (d, J =8.21 Hz, 1H), 12.27 (s, 1H) 156 (400 MHz, DMSO-D6) 0.71 (d, J = 6.94 Hz,3H), 1.03 405 403 (d, J = 6.94 Hz, 3H), 1.47-1.57 (m, 2H), 1.60 (s, 3H),1.62-1.70 (m, 2H), 1.73-1.79 (m, 2H), 1.93-2.00 (m, 3H), 2.35-2.41 (m,2H), 3.28-3.34 (m, 1H), 3.51 (dd, J = 13.87, 7.17 Hz, 1H), 3.59 (dd, J =13.87, 7.17 Hz, 1H), 6.12 (s, 1H), 6.98 (s, 1H), 7.29 (dd, J = 8.09,1.85 Hz, 1H), 7.35 (d, J = 1.94 Hz, 1H), 7.35 (d, J = 8.21 Hz, 1H),12.39 (s, 1H) 157 (400 MHz, CDCl3) 0.67-0.75 (m, 3H), 1.00-1.08 409 407(m, 3H), 1.21-1.28 (m, 6H), 1.70 (s, 3H), 1.82-1.95 (m, 1H), 2.60-2.66(m, 2H), 3.68-3.82 (m, 3H), 4.56 (s, 2H), 5.40-5.66 (m, 1H), 5.88 (s,1H), 7.31-7.42 (m, 2H), 7.45-7.52 (m, 1H) 158 (400 MHz, CDCl3) δ: 0.03(d, J = 2.82 Hz, 9H), 0.70 437 435 (d, J = 6.85 Hz, 3H), 0.81-0.85 (m,2H), 1.04 (d, J = 6.85 Hz, 3H), 1.70 (s, 3H), 1.83-1.90 (m, 1H), 2.67(dt, J = 14.78, 5.44 Hz, 4H), 3.71-3.82 (m, 2H), 5.50 (s, 1H), 5.87 (s,1H), 7.20 (d, J = 8.06 Hz, 1H), 7.25 (d, J = 2.01 Hz, 2H), 7.37 (d, J =2.01 Hz, 1H). 159 (400 MHz, DMSO-D6) 0.73-0.78 (m, 3H), 0.96 (s, 469 4679H), 1.07-1.13 (m, 3H), 1.35-1.44 (m, 2H), 1.72 (s, 3H), 2.01-2.09 (m,1H), 2.60-2.70 (m, 2H), 6.39 (s, 1H), 7.30-7.40 (m, 2H), 7.41-7.47 (m,3H), 7.54-7.59 (m, 1H), 7.91-7.96 (m, 2H) 160 (400 MHz, CDCl3) 0.79 (s,3H), 0.90 (m, 9H), 1.04 479 477 (d, J = 9.02 Hz, 3H), 1.11-1.39 (m, 3H),1.43 (m, 2H), 1.94 (s, 3H), 2.19 (m, 1H), 2.27-2.34 (m, 1H), 2.61-2.65(m, 2H), 3.38 (mz, 4H), 3.48-3.54 (m, 2H), 6.11 (s, 1H), 6.66 (s, 1H),7.11 (d, J = 8.09 Hz, 1H), 7.25 (m, 2H), 7.38 (d, J = 1.85 Hz, 1H) 161(400 MHz, DMSO-D6) 0.69 (d, J = 6.85 Hz, 3H), 1.03 461 459 (d, J = 6.85Hz, 3H), 1.59 (s, 3H), 1.95 (qq, J = 6.85, 6.85 Hz, 1H), 2.44 (dd, J =6.85, 6.85 Hz, 2H), 3.50 (dt, J = 13.50, 6.85 Hz, 1H), 3.64 (dt, J =13.50, 6.85 Hz, 1H), 5.12 (s, 2H), 6.12 (s, 1H), 7.09 (s, 1H), 7.22 (dd,J = 12.40, 2.50 Hz, 2H), 7.25 (dd, J = 2.50, 1.41 Hz, 2H), 7.34-7.40 (m,3H), 7.43-7.46 (m, 2H) 162 (400 MHz, DMSO-D6) 0.71 (d, J = 6.85 Hz, 3H),0.95 490 488 (s, 9H), 1.03 (d, J = 6.85 Hz, 3H), 1.36-1.40 (m, 2H), 1.62(s, 3H), 1.98 (qq, J = 6.85, 6.85 Hz, 1H), 2.26-2.32 (m, 1H), 2.60-2.65(m, 2H), 2.65-2.71 (m, 1H), 3.35-3.38 (m, 1H), 3.67-3.72 (m, 1H), 3.85(d, J = 17.33 Hz, 1H), 4.07 (d, J = 17.33 Hz, 1H), 5.02-5.09 (m, 1H),6.22 (s, 1H), 7.19 (s, 1H), 7.27 (dd, J = 8.06, 2.01 Hz, 1H), 7.30 (d, J= 8.06 Hz, 1H), 7.35 (d, J = 2.01 Hz, 1H) 163 (400 MHz, DMSO-D6) 0.73(d, J = 6.85 Hz, 3H), 0.95 490 488 (s, 9H), 1.07 (d, J = 6.85 Hz, 3H),1.36-1.41 (m, 2H), 1.62 (s, 3H), 1.98 (qq, J = 6.85, 6.85 Hz, 1H),2.18-2.24 (m, 1H), 2.60-2.65 (m, 2H), 2.67-2.74 (m, 1H), 3.35-3.39 (m,1H), 3.68-3.73 (m, 1H), 3.83 (d, J = 17.73 Hz, 1H), 4.10 (d, J = 17.73Hz, 1H), 5.03-5.09 (m, 1H), 6.28 (s, 1H), 7.21 (s, 1H), 7.25 (dd, J =8.06, 2.01 Hz, 1H), 7.31 (d, J = 8.06 Hz, 1H), 7.34 (d, J = 2.01 Hz, 1H)164 (400 MHz, DMSO-D6) 0.72 (d, J = 6.85 Hz, 3H), 1.02 441 439 (s, 9H),1.03 (d, J = 6.85 Hz, 3H), 1.60 (s, 3H), 1.97 (qq, J = 6.85, 6.85 Hz,1H), 2.43 (dd, J = 7.05, 7.05 Hz, 2H), 3.50 (dt, J = 13.50, 7.05 Hz,1H), 3.64 (dt, J = 13.50, 7.05 Hz, 1H), 3.73 (s, 2H), 6.13 (s, 1H), 7.09(s, 1H), 7.21 (dd, J = 12.49, 2.42 Hz, 1H), 7.25 (dd, J = 2.42, 1.21 Hz,1H) 165 (400 MHz, DMSO-D6) 0.72 (d, J = 6.85 Hz, 3H), 0.94 455 453 (s,9H), 1.03 (d, J = 6.85 Hz, 3H), 1.60 (s, 3H), 1.67 (t, J = 7.45 Hz, 2H),1.97 (qq, J = 6.85, 6.85 Hz, 1H), 2.44 (dd, J = 6.85, 6.85 Hz, 2H), 3.50(dt, J = 13.50, 6.85 Hz, 1H), 3.64 (dt, J = 13.50, 6.85 Hz, 1H), 4.09(t, J = 7.45 Hz, 2H), 6.13 (s, 1H), 7.09 (s, 1H), 7.22 (dd, J = 12.29,2.22 Hz, 1H), 7.26 (dd, J = 2.22, 1.41 Hz, 1H) 166 (400 MHz, DMSO-D6)0.69 (d, J = 7.00 Hz, 3H), 0.93 447 445 (s, 3H), 1.01 (s, 3H), 1.02 (d,J = 7.00 Hz, 3H), 1.17-1.35 (m, 3H), 1.38-1.46 (m, 2H), 1.55-1.74 (m,6H), 1.89-1.96 (m, 1.H), 2.45 (t, J = 6.76 Hz, 2H), 3.07-3.15 (m, 1H),3.48-3.55 (m, 1H), 3.58-3.65 (m, 1H), 6.11 (s, 1H), 7.02 (s, 1H),7.28-7.34 (m, 3H), 12.25 (brs, 1H) 167 (400 MHz, DMSO-D6) 0.69 (d, J =6.76 Hz, 3H), 0.93 447 445 (s, 3H), 1.01 (s, 3H), 1.02 (d, J = 6.76 Hz,3H), 1.15-1.35 (m, 3H), 1.38-1.46 (m, 2H), 1.54-1.74 (m, 6H), 1.89-1.96(m, 1H), 2.45 (t, J = 6.76 Hz, 3H), 3.08-3.17 (m, 1H), 3.48-3.55 (m,1H), 3.58-3.65 (m, 1H), 6.11 (s, 1H), 7.01 (s, 1H), 7.28-7.34 (m, 3H),12.25 (brs, 1H) 168 (400 MHz, CDCl3) 0.97 (s, 9H), 1.41-1.50 (m, 2H),463 461 1.63 (s, 3H), 1.76-1.96 (m, 3H), 2.03-2.18 (m, 1H), 2.24-2.35(m, 1H), 2.38-2.51 (m, 1H), 2.61-2.71 (m, 2H), 2.74-2.88 (m, 1H), 3.38(s, 3H), 3.53-3.60 (m, 2H), 3.61-3.75 (m, 2H), 5.08-5.42 (m, 1H), 5.93(s, 1H), 7.12-7.24 (m, 2H), 7.35-7.39 (m, 1H) 169 (400 MHz, DMSO-D6)0.70 (d, J = 6.94 Hz, 3H), 0.86-0.94 433 431 (m, 3H), 0.90 (s, 9H), 1.02(d, J = 6.94 Hz, 3H), 1.59 (s, 3H), 1.90-1.95 (m, 1H), 1.99-2.05 (m,1H), 2.44 (t, J = 6.70 Hz, 2H), 3.47-3.54 (m, 1H), 3.58-3.65 (m, 1H),6.11 (s, 1H), 6.97 (d, J = 8.55 Hz, 1H), 6.98 (s, 1H), 7.23 (dd, J =8.21, 1.97 Hz, 1H), 7.33 (d, J = 2.08 Hz, 1H), 12.28 (s, 1H) 170 (400MHz, DMSO-D6) 0.71 (d, J = 6.94 Hz, 3H), 0.85-0.94 433 431 (m, 3H), 0.90(s, 9H), 1.03 (d, J = 6.70 Hz, 3H), 1.59 (s, 3H), 1.94 (t, J = 6.94 Hz,1H), 1.99-2.04 (m, 1H), 2.35-2.40 (m, 2H), 3.50 (dd, J = 13.99, 6.82 Hz,1H), 3.59 (dd, J = 13.99, 6.82 Hz, 1H), 6.11 (s, 1H), 6.96 (d, J = 8.28Hz, 1H), 6.97 (s, 1H), 7.22 (dd, J = 8.09, 1.85 Hz, 1H), 7.34 (d, J =1.85 Hz, 1H), 12.35 (s, 1H) 171 (400 MHz, CDCl3) 0.30-0.40 (m, 2H), 0.51(m, 1H), 433 431 0.78 (s, 3H), 0.92-1.00 (m, 9H), 1.40-1.45 (m, 2H),1.79 (s, 4H), 2.65 (m, 5H), 3.67-3.78 (m, 1H), 5.31 (s, 1H), 6.11 (s,1H), 7.14 (d, J = 8.09 Hz, 1H), 7.21 (d, J = 2.08 Hz, 1H), 7.24 (m, 1H),7.37 (d, J = 2.08 Hz, 1H) 172 (400 MHz, CDCl3) 0.85 (s, 3H), 0.97 (s,9H), 1.13 (s, 463 461 3H), 1.21 (d, J = 4.84 Hz, 3H), 1.23 (d, J = 4.84Hz, 3H), 1.34-1.39 (m, 1H), 1.42-1.46 (m, 2H), 1.97 (s, 3H), 2.12-2.25(m, 2H), 2.35-2.27 (m, 1H), 2.66-2.62 (m, 2H), 4.59-4.52 (m, 1H), 6.16(s, 1H), 6.58 (s, 1H), 7.13 (d, J = 8.06 Hz, 1H), 7.23 (dd, J = 8.06,2.01 Hz, 1H), 7.36 (d, J = 2.01 Hz, 1H) 173 (400 MHz, DMSO-D6) 0.69 (d,J = 6.94 Hz, 3H), 1.02 431 429 (d, J = 6.70 Hz, 3H), 1.60 (s, 3H),1.77-2.04 (m, 7H), 2.12 (t, J = 6.82 Hz, 2H), 2.38-2.47 (m, 4H),3.46-3.56 (m, 2H), 3.62 (dt, J = 13.60, 6.80 Hz, 1H), 6.11 (s, 1H), 7.01(s, 1H), 7.28-7.33 (m, 3H), 12.27 (brs, 1H) 174 (400 MHz, DMSO-D6) 0.70(d, J = 6.70 Hz, 3H), 0.78-0.88 419 417 (m, 2H), 0.88-0.95 (m, 1H), 0.98(d, J = 6.70 Hz, 3H), 1.02 (t, J = 6.13 Hz, 6H), 1.14-1.21 (m, 1H), 1.59(s, 3H), 1.93 (dd, J = 12.37, 6.13 Hz, 2H), 2.35-2.43 (m, 2H), 3.50 (dd,J = 13.76, 6.59 Hz, 1H), 3.59 (dd, J = 13.76, 7.05 Hz, 1H), 6.11 (s,1H), 6.93 (d, J = 8.32 Hz, 1H), 6.96 (s, 1H), 7.22 (dd, J = 8.21, 1.97Hz, 1H), 7.33 (d, J = 2.08 Hz, 1H), 12.46 (s, 1H) 175 (400 MHz, DMSO-D6)0.71 (d, J = 6.85 Hz, 3H), 0.95 439 437 (s, 9H), 1.03 (d, J = 6.85 Hz,3H), 1.31-1.35 (m, 2H), 1.60 (s, 3H), 1.97 (qq, J = 6.85, 6.85 Hz, 1H),2.43 (dd, J = 6.85, 6.85 Hz, 2H), 2.64-2.69 (m, 2H), 3.50 (dt, J =13.50, 6.85 Hz, 1H), 3.63 (dt, J = 13.50, 6.85 Hz, 1H), 6.14 (s, 1H),7.09 (s, 1H), 7.12 (dd, J = 11.08, 1.81 Hz, 1H), 7.24 (dd, J = 1.81,1.01 Hz, 1H) 176 (400 MHz, DMSO-D6) 0.67 (d, J = 6.85 Hz, 3H), 0.93 405403 (s, 9H), 1.02 (d, J = 6.85 Hz, 3H), 1.38-1.42 (m, 2H), 1.60 (s, 3H),1.94 (qq, J = 6.85, 6.85 Hz, 1H), 2.44 (dd, J = 6.85, 6.85 Hz, 2H),2.52-2.55 (m, 2H), 3.51 (dt, J = 13.50, 6.85 Hz, 1H), 3.62 (dt, J =13.50, 6.85 Hz, 1H), 6.09 (s, 1H), 6.99 (s, 1H), 7.07 (dd, J = 11.89,2.01 Hz, 1H), 7.12 (dd, J = 8.06, 2.01 Hz, 1H), 7.23 (dd, J = 8.06, 4.03Hz, 1H) 177 (400 MHz, DMSO-D6) 0.65 (d, J = 6.82 Hz, 3H), 0.84 421 419(t, J = 7.51 Hz, 6H), 1.02 (d, J = 6.82 Hz, 3H), 1.20-1.30 (m, 4H),1.53-1.56 (m, 1H), 1.61 (s, 3H), 1.88-1.95 (m, 1H), 2.45 (t, J = 6.80Hz, 2H), 2.59 (d, J = 7.17 Hz, 2H), 3.52 (dt, J = 14.00, 6.80 Hz, 2H),3.62 (dt, J = 14.00, 6.80 Hz, 2H), 6.09 (s, 1H), 7.04 (bs, 1H), 7.24 (d,J = 8.09 Hz, 2H), 7.27 (dd, J = 8.09, 1.74 Hz, 2H), 7.35 (d, J = 1.74Hz, 1H), 12.31 (bs, 1H) 178 (400 MHz, DMSO-D6) 0.63 (d, J = 6.94 Hz,3H), 0.81 449 447 (t, J = 6.70 Hz, 6H), 1.01 (d, J = 6.94 Hz, 3H),1.13-1.35 (m, 8H), 1.61 (s, 3H), 1.67-1.70 (m, 1H), 1.87-1.94 (m, 1H),2.45 (t, J = 6.80 Hz, 2H), 2.59 (d, J = 7.17 Hz, 2H), 3.53 (dt, J =14.00, 6.80 Hz, 1H), 3.62 (dt, J = 14.00, 6.80 Hz, 1H), 6.08 (s, 1H),7.05 (bs, 1H), 7.23 (t, J = 3.93 Hz, 1H), 7.25-7.29 (m, 1H), 7.35 (d, J= 1.85 Hz, 1H), 12.29 (bs, 1H) 179 (400 MHz, DMSO-D6) 0.598 (d, J = 7.20Hz, 1.5H), 435 433 0.600 (d, J = 7.20 Hz, 1.5H), 0.99 (d, J = 6.70 Hz,3H), 1.11 (d, J = 7.20 Hz, 1.5H), 1.12 (d, J = 7.20 Hz, 1.5H), 1.46(ddd, J = 14.05, 3.93, 0.92 Hz, 1H), 1.58 (s, 3H), 1.75 (dd, J = 14.05,8.79 Hz, 1H), 1.87-1.90 (m, 1H), 2.42-2.44 (m, 2H), 2.48-2.49 (m, 1H),3.51 (dt, J = 14.00, 6.80 Hz, 1H), 3.61 (dt, J = 14.00, 6.80 Hz, 1H),6.06 (s, 1H), 6.98 (s, 0.5H), 7.00 (s, 0.5H), 7.27-7.31 (m, 2H),7.36-7.38 (m, 1H) 180 (400 MHz, CDCl3) 0.90 (s, 3H), 0.96-1.02 (m, 18H),505 503 1.29-1.52 (m, 4H), 1.80 (s, 3H), 2.51-2.72 (m, 8H), 2.96-3.10(m, 1H), 3.44-3.60 (m, 2H), 4.94-5.06 (m, 1H), 5.07-5.18 (m, 1H), 6.16(s, 1H), 7.13-7.20 (m, 2H), 7.21-7.28 (m, 1H), 7.40-7.45 (m, 1H) 181(400 MHz, CDCl3) 0.82 (s, 3H), 0.96 (s, 9H), 1.15 (s, 533 531 3H),1.36-1.47 (m, 2H), 1.99 (s, 3H), 2.18-2.36 (m, 2H), 2.50-2.78 (m, 8H),2.97-3.10 (m, 1H), 3.72 (s, 3H), 4.77-4.90 (m, 1H), 6.24 (s, 1H), 7.02(brs, 1H), 7.08-7.14 (m, 1H), 7.17-7.21 (m, 1H), 7.31-7.33 (m, 1H) 182(400 MHz, CDCl3) 0.77 (s, 3H), 0.94 (s, 9H), 1.13 (s, 505 503 3H),1.33-1.50 (m, 3H), 1.97 (s, 3H), 2.07-2.50 (m, 6H), 2.57-2.71 (m, 2H),3.70-3.75 (m, 2H), 4.78-4.89 (m, 1H), 6.31 (s, 1H), 6.91 (brs, 1H),7.07-7.13 (m, 1H), 7.13-7.21 (m, 1H), 7.29-7.35 (m, 1H) 183 (400 MHz,DMSO-D6) 0.69 (d, J = 6.85 Hz, 3H), 0.99 409 407 (d, J = 6.45 Hz, 6H),1.02 (d, J = 6.85 Hz, 3H), 1.59 (s, 3H), 1.92 (qq, J = 6.85, 6.85 Hz,1H), 2.03 (tsep, J = 6.45, 6.45 Hz, 1H), 2.45 (dd, J = 7.05, 7.05 Hz,2H), 3.52 (dt, J = 13.50, 7.05 Hz, 1H), 3.62 (dt, J = 13.50, 7.05 Hz,1H), 3.81 (d, J = 6.45 Hz, 2H), 6.09 (s, 1H), 6.98 (s, 1H), 7.07 (d, J =8.87 Hz, 1H), 7.26 (dd, J = 8.87, 2.42 Hz, 1H), 7.36 (d, J = 2.42 Hz,1H) 184 (400 MHz, CDCl3) 0.85 (d, J = 15.26 Hz, 3H), 0.96 (s, 475 4739H), 1.10 (s, 6H), 1.24-1.77 (m, 8H), 1.90 m, 2H), 2.14-2.31 (m, 2H),2.61-2.65 (m, 2H), 4.72 (m, 1H), 6.08 (s, 1H), 6.30 (s, 1H), 7.12 (d, J= 7.63 Hz, 1H), 7.21 (t, J = 3.93 Hz, 1H), 7.25 (t, J = 1.50 Hz, 1H),7.35 (s, 1H) 185 (400 MHz, DMSO-D6) 0.64-0.70 (m, 3H), 0.98-1.03 475 473(m, 3H), 1.16 (s, 6H), 1.58 (s, 3H), 1.60-1.67 (m, 2H), 1.85-1.99 (m,1H), 2.35-2.42 (m, 2H), 2.66-2.74 (m, 2H), 3.43-3.55 (m, 1H), 3.55-3.65(m, 1H), 6.10 (s, 1H), 7.00 (s, 1H), 7.21-7.39 (m, 3H) 186 (400 MHz,DMSO-D6) 0.64-0.70 (m, 3H), 0.94 (s, 459 457 9H), 0.99-1.04 (m, 3H),1.33-1.41 (m, 2H), 1.58 (s, 3H), 1.85-2.00 (m, 7H), 2.58-2.64 (m, 2H),4.00-4.35 (m, 1H), 5.93 (s, 1H), 6.86 (s, 1H), 7.19-7.34 (m, 3H) 187(400 MHz, CDCl3) 0.97 (s, 9H), 1.33 (s, 9H), 1.90-2.03 431 429 (m, 2H),2.32-2.45 (m, 2H), 3.40-3.47 (m, 1H), 3.67-3.74 (m, 1H), 4.84 (d, J =2.87 Hz, 1H), 5.50-5.59 (brm, 1H), 6.11 (s, 1H), 7.05 (dd, J = 7.94,1.76 Hz, 1H), 7.25 (d, J = 1.76 Hz, 1H), 7.38 (d, J = 7.94 Hz, 1H) 188(400 MHz, DMSO-D6) 0.67 (d, J = 6.85 Hz, 3H), 1.03 371 369 (d, J = 6.85Hz, 3H), 1.63 (s, 3H), 1.67-1.74 (m, 2H), 1.82 (s, 3H), 1.87 (s, 3H),1.96 (qq, J = 6.85, 6.85 Hz, 1H), 2.18 (t, J = 7.45 Hz, 2H), 3.28-3.34(m, 1H), 3.40-3.47 (m, 1H), 6.01 (s, 1H), 6.24 (s, 1H), 6.91 (s, 1H),7.18 (d, J = 8.46 Hz, 2H), 7.34 (d, J = 8.46 Hz, 2H) 189 (400 MHz,DMSO-D6) 0.72 (d, J = 6.85 Hz, 3H), 1.04 437 435 (d, J = 6.85 Hz, 3H),1.11 (s, 9H), 1.61 (s, 3H), 1.98 (qq, J = 6.85, 6.85 Hz, 1H), 2.44 (dd,J = 7.05, 7.05 Hz, 2H), 3.51 (dt, J = 13.50, 7.05 Hz, 1H), 3.64 (dt, J =13.50, 7.05 Hz, 1H), 6.14 (s, 1H), 6.29 (d, J = 16.52 Hz, 1H), 6.44 (d,J = 16.52 Hz, 1H), 7.13 (s, 1H), 7.17 (dd, J = 12.29, 1.81 Hz, 1H), 7.28(d, J = 1.81 Hz, 1H)

TABLE 4 MS M + H or M − H or Example ¹H-NMR M − Na + H M − Na − H 190(400 MHz, CDCl₃) 0.90 (s, 3H), 0.97 (s, 9H), 1.00 (s, 519 517 3H),1.24-1.40 (m, 2H), 1.40-1.51 (m, 3H), 1.79 (s, 3H), 2.56-2.73 (m, 6H),3.00-3.11 (m, 1H), 3.43- 3.60 (m, 2H), 3.73 (s, 3H), 4.48-4.53 (m, 1H),4.89- 5.03 (m, 1H), 6.14 (s, 1H), 7.14-7.18 (m, 1H), 7.24- 7.29 (m, 1H),7.42-7.46 (m, 1H) 191 (400 MHz, CDCl₃) 0.90 (s, 3H), 0.97 (s, 9H), 1.00(s, 519 517 3H), 1.24-1.40 (m, 2H), 1.40-1.51 (m, 3H), 1.79 (s, 3H),2.56-2.73 (m, 6H), 3.00-3.11 (m, 1H), 3.43- 3.60 (m, 2H), 3.73 (s, 3H),4.48-4.53 (m, 1H), 4,89- 5.03 (m, 1H), 6.34 (s, 1H), 7.14-7.18 (m, 1H),7.24- 7.29 (m, 1H), 7.42-7.46 (m, 1H) 192 (400 MHz, DMSO-D₆) 0.73-0.79(m, 3H), 0.88- 489 487 0.93 (m, 6H), 1.05-1.11 (m, 3H), 1.55-1.63 (m,2H), 1.70 (s, 3H), 1.77-1.88 (m, 1H), 2.02-2.13 (m, 1H), 4.05-4.11 (m,2H), 6.35 (s, 1H), 7.27-7.38 (m, 4H), 7.51-7.55 (m, 1H), 7.85-7.91 (m,2H) 193 (400 MHz, DMSO-D₆) 0.72-0.78 (m, 3H), 1.01 (s, 489 487 9H),1.06-1.10 (m, 3H), 1.70 (s, 3H), 2.03-2.12 (m, 1H), 3.73-3.75 (m, 2H),6.33 (s, 1H), 7.24-7.36 (m, 4H), 7.46-7.52 (m, 1H), 7.82-7.89 (m, 2H)194 (400 MHz, DMSO-D₆) 0.72 (d, J = 6.85 Hz, 3H), 0.99 427 425 (d, J =6.45 Hz, 6H), 1.03 (d, J = 6.45 Hz, 3H), 1.60 (s, 3H), 1.93-2.05 (m,2H), 2.44 (t, J = 7.05 Hz, 2H), 3.50 (dt, J = 13.50, 7.05 Hz, 1H), 3.64(dt, J = 13.50, 7.05 Hz, 1H), 3.83 (d, J = 6.25 Hz, 2H), 6.13 (s, 1H),7.09 (s, 1H), 7.21 (dd, J = 12.29, 2.22 Hz, 1H), 7.25 (dd, J = 2.22,1.41 Hz, 1H) 195 (400 MHz, DMSO-D₆) 0.72 (d, J = 6.85 Hz, 3H), 0.92 441439 (d, J = 6.85 Hz, 6H), 1.03 (d, J = 6.85 Hz, 3H), 1.57-1.62 (m, 2H),1.60 (s, 3H), 1.78-1.88 (m, 1H), 1.93-2.00 (m, 1H), 2.44 (t, J = 6.85Hz, 2H), 3.50 (dt, J = 13.50, 6.85 Hz, 1H), 3.64 (dt, J = 13.50, 6.85Hz, 1H), 4.07 (t, J = 6.45 Hz, 2H), 6.13 (s, 1H), 7.09 (s, 1H), 7.22(dd, J = 12.29, 2.22 Hz, 1H), 7.26 (dd, J = 2.22, 1.41 Hz, 1H) 196 (400MHz, DMSO-D₆) 0.71-0.77 (m, 3H), 1.06- 523 521 1.11 (m, 3H), 1.14-1.18(m, 6H), 1.61-1.69 (m, 2H), 1.72 (s, 3H), 2.01-2.09 (m, 1H), 2.68-2.77(m, 2H), 6.39 (s, 1H), 7.36-7.40 (m, 2H), 7.41-7.49 (m, 3H), 7.55-7.58(m, 1H), 7.91-7.95 (m, 2H), 12.86 (brs, 1H) 197 (400 MHz, CDCl₃) 0.83(s, 3H), 0.97 (s, 9H), 1.14 (s, 505 503 3H), 1.33-1.40 (m, 1H),1.41-1.48 (m, 2H), 1.97 (s, 3H), 2.11-2.34 (m, 3H), 2.34-2.46 (m, 3H),2.46- 2.57 (m, 1H), 2.59-2.69 (m, 2H), 3.26 (s, 3H), 3.97- 4.04 (m, 1H),4.77-4.87 (m, 1H), 6.22 (s, 1H), 6.81 (brs, 1H), 7.10-7.15 (m, 1H),7.19-7.22 (m, 1H), 7.32-7.35 (m, 1H) 198 (400 MHz, DMSO-D₆) 0.81 (s,3H), 0.94 (s, 9H), 0.98 519 517 (s, 3H), 1.35-1.40 (m, 3H), 1.74 (s,3H), 1.76-1.83 (m, 1H), 1.93-1.99 (m, 2H), 2.04-2.08 (m, 2H), 2.25- 2.40(m, 3H), 2.59-2.63 (m, 2H), 3.28 (s, 3H), 3.40 (d, J = 6.45 Hz, 2H),4.88-4.80 (m, 1H), 6.34 (s, 1H), 6.92 (s, 1H), 7.22 (dd, J = 8.06, 2.01Hz, 1H), 7.27 (d, J = 8.06 Hz, 1H), 7.32 (d, J = 2.01 Hz, 1H) 199 (400MHz, CDCl₃) 0.77-0.91 (m, 2H), 0.96-0.99 489 487 (m, 9H), 1.40-1.49 (m,2H), 1.61-1.66 (m, 3H), 1.69- 1.76 (m, 1H), 1.77-1.94 (m, 2H), 2.09-2.19(m, 1H), 2.27-2.37 (m, 1H), 2.43-2.53 (m, 1H), 2.61- 2.71 (m, 1H),2.78-2.92 (m, 1H), 3.47-3.57 (m, 2H), 4.01-4.11 (m, 2H), 4.51-4.63 (m,1H), 5.12 (brs, 1H), 5.96 (brs, 1H), 7.15-7.19 (m, 2H), 7.33-7.34 (m,1H) 200 (400 MHz, CDCl₃) 0.98 (s, 9H), 1.41-1.47 (m, 2H), 489 4871.62-1.66 (m, 3H), 1.79-1.98 (m, 3H), 2.09-2.21 (m, 1H), 2.39-2.54 (m,5H), 2.62-2.71 (m, 2H), 2.81- 2.92 (m, 1H), 3.26-3.30 (m, 3H), 3.99-4.06(m, 1H), 4.84-4.90 (m, 1H), 4.92-5.02 (m, 1H), 5.98- 6.00 (m, 1H),7.14-7.23 (m, 2H), 7.33-7.36 (m, 1H) 201 (400 MHz, CDCl₃) 0.74-0.85 (m,6H), 1.05 (s, 9H), 455 453 1.47-1.63 (m, 2H), 1.66-1.75 (m, 4H),2.61-2.68 (m, 2H), 3.59-3.66 (m, 2H), 3.67-3.77 (m, 2H), 5.30 (brs, 1H),5.79 (s, 1H), 6.56-6.62 (m, 1H), 7.03-7.10 (m, 1H) 202 (400 MHz, CDCl₃)0.74-0.85 (m, 6H), 0.91-1.01 455 453 (m, 6H), 1.45-2.09 (m, 9H),2.60-2.69 (m, 2H), 3.68- 3.78 (m, 2H), 4.00-4.07 (m, 2H), 5.19 (brs,1H), 5.79 (s, 1H), 6.58-6.65 (m, 1H), 7.03-7.12 (m, 1H) 203 (400 MHz,DMSO-D₆) 0.75-0.80 (m, 3H), 1.09- 471 469 1.13 (m, 3H), 1.24 (s, 9H),1.74 (s, 3H), 2.03-2.13 (m, 1H), 4.45 (s, 2H), 6.41 (s, 1H), 7.41-7.54(m, 5H), 7.58-7.62 (m, 1H), 7.92-7.97 (m, 2H), 12.88 (brs, 1H) 204 (400MHz, DMSO-D₆) 0.64-0.72 (m, 3H), 0.94 (s, 483 481 9H), 0.98-1.03 (m,3H), 1.35-1.38 (m, 2H), 1.96- 2.05 (m, 3H), 2.57-2.65 (m, 2H), 4.48-4.57(m, 1H), 4.70-4.79 (m, 2H), 6.14 (s, 1H), 7.17-7.36 (m, 6H), 7.84-7.89(m, 2H), 12.88 (brs, 1H) 205 (400 MHz, DMSO-D₆) 0.95 (s, 9H), 1.34-1.41(m, 489 487 2H), 1.43-1.51 (m, 1H), 1.51-1.54 (m, 3H), 1.57- 1.67 (m,2H), 2.02-2.15 (m, 2H), 2.23-2.34 (m, 4H), 2.58-2.65 (m, 2H), 2.84-2.95(m, 1H), 3.23-3.28 (m, 2H), 4.32-4.37 (m, 1H), 4.88-4.99 (m, 1H), 6.17(s, 1H), 7.12-7.14 (m, 1H), 7.18-7.24 (m, 1H), 7.26- 7.31 (m, 2H), 12.24(brs, 1H) 206 (400 MHz, CDCl₃) 0.94-1.01 (m, 9H), 1.40-1.49 477 475 (m,2H), 1.53-1.68 (m, 5H), 2.05-2.17 (m, 1H), 2.17- 2.29 (m, 1H), 2.29-2.43(m, 1H), 2.58-2.69 (m, 5H), 3.20-3.24 (m, 2H), 3.27-3.30 (m, 3H), 3.66-3.79 (m, 1H), 3.79-3.90 (m, 1H), 5.53-5.64 (m, 1H), 5.79-5.82 (m, 1H),7.12-7.23 (m, 2H), 7.31-7.36 (m, 1H) 207 (400 MHz, DMSO-D₆) 0.68-0.72(m, 3H), 0.96 (s, 487 485 9H), 1.03-1.09 (m, 3H), 1.37-1.43 (m, 2H),1.73 (s, 3H), 1.98-2.08 (m, 1H), 2.61-2.69 (m, 2H), 6.20 (s, 1H),7.32-7.46 (m, 3H), 7.46-7.49 (m, 1H), 7.51- 7.56 (m, 1H), 7.65-7.72 (m,1H), 7.72-7.78 (m, 1H) 208 (400 MHz, CDCl₃) 0.68-0.79 (m, 3H), 0.98(brs, 487 485 9H), 1.03-1.09 (m, 3H), 1.39-1.49 (m, 2H), 1.72- 1.80 (m,3H), 1.87-2.00 (m, 1H), 2.61-2.72 (m, 2H), 5.51-5.77 (m, 1H), 6.00-6.10(m, 1H), 7.00-7.12 (m, 1H), 7.14-7.24 (m, 1H), 7.28-7.35 (m, 1H), 7.37-7.51 (m, 2H), 7.84-7.99 (m, 1H) 209 (400 MHz, DMSO-D₆) 0.75-0.79 (m,3H), 0.79- 541 539 0.83 (m, 3H), 0.95 (s, 9H), 1.34-1.44 (m, 4H), 1.66(s, 3H), 1.84-1.95 (m, 2H), 2.60-2.67 (m, 2H), 3.15 (s, 3H), 3.24-3.29(m, 2H), 6.39 (s, 1H), 7.32-7.36 (m, 2H), 7.41-7.44 (m, 2H), 7.44-7.46(m, 1H), 7.64- 7.69 (m, 1H), 7.91-7.97 (m, 2H) 210 (400 MHz, DMSO-D₆)0.96 (s, 9H), 1.35-1.43 (m, 485 483 2H), 1.69 (s, 3H), 1.96-2.09 (m,1H), 2.13-2.22 (m, 1H), 2.60-2.69 (m, 2H), 3.12 (s, 3H), 3.18-3.29 (m,2H), 6.39 (s, 1H), 7.32-7.39 (m, 2H), 7.42-7.48 (m, 3H), 7.63-7.67 (m,1H), 7.90-7.97 (m, 2H), 12.89 (brs, 1H) 211 (400 MHz, CDCl₃) 0.98 (s,9H), 1.40-1.48 (m, 2H), 437 435 1.68 (s, 3H), 1.84-1.95 (m, 1H),2.00-2.11 (m, 1H), 2.59-2.70 (m, 4H), 3.14-3.27 (m, 5H), 3.67-3.88 (m,2H), 5.53 (brs, 1H), 5.91-5.93 (m, 1H), 7.15- 7.19 (m, 1H), 7.22-7.26(m, 1H), 7.37-7.39 (m, 1H) 212 (400 MHz, DMSO-D₆) 0.72 (d, J = 6.94 Hz,3H), 0.92 417 415 (s, 9H), 1.03 (d, J = 6.94 Hz, 3H), 1.32-1.38 (m, 2H),1.61 (s, 3H), 1.91-1.98 (m, 1H), 2.43-2.49 (m, 4H), 3.45-3.52 (m, 1H),3.61-3.69 (m, 1H), 3.75 (s, 3H), 6.08 (s, 1H), 6.87 (dd, J = 7.74, 1.73Hz, 1H), 6.89- 6.92 (m, 2H), 7.05 (d, J = 7.86 Hz, 1H), 12.24 (s, 1H)213 (400 MHz, DMSO-D₆) 0.72 (d, J = 6.94 Hz, 3H), 0.92 417 415 (s, 9H),1.03 (d, J = 6.94 Hz, 3H), 1.32-1.38 (m, 2H), 1.61 (s, 3H), 1.94 (t, J =6.70 Hz, 1H), 2.43-2.49 (m, 4H), 3.45-3.52 (m, 1H), 3.62-3.69 (m, 1H),3.75 (s, 3H), 6.08 (s, 1H), 6.87 (dd, J = 7.74, 1.73 Hz, 1H), 6.89- 6.92(m, 2H), 7.05 (d, J = 7.86 Hz, 1H), 12.26 (s, 1H) 214 (400 MHz, CDCl₃)0.70 (d, J = 6.94 Hz, 3H), 1.03 (t, 425 423 J = 5.20 Hz, 6H), 1.06 (d, J= 6.70 Hz, 6H), 1.88 (tt, J = 19.19, 6.40 Hz, 2H), 2.66 (t, J = 6.24 Hz,2H), 2.80 (d, J = 6.94 Hz, 2H), 3.76 (t, J = 6.47 Hz, 2H), 5.19 (s, 1H),5.86 (s, 1H), 7.18 (d, J = 8.32 Hz, 1H), 7.28 (dd, J = 8.44, 1.97 Hz,1H), 7.39 (d, J = 2.08 Hz, 1H) 215 (400 MHz, CDCl₃) 0.69 (t, J = 6.59Hz, 3H), 1.06 (d, 441 439 J = 6.70 Hz, 6H), 1.20 (d, J = 6.70 Hz, 6H),1.88 (dt, J = 19.34, 6.70 Hz, 2H), 2.60 (tt, J = 17.11, 5.39 Hz, 2H),2.83 (dd, J = 12.95, 9.94 Hz, 2H), 3.76 (ddd, J = 44.74, 20.46, 12.60Hz, 2H), 5.69 (d, J = 27.51 Hz, 1H), 5.91 (s, 1H), 7.45 (dd, J = 18.84,1.73 Hz, 1H), 7.58 (ddd, J = 20.29, 8.38, 1.79 Hz, 1H), 7.86 (dd, J =10.52, 8.21 Hz, 1H) 216 ¹H-NMR (CDCl₃) δ: 0.71 (d, J = 6.94 Hz, 3H),0.87 (t, 471 469 J = 3.24 Hz, 6H), 1.07 (d, J = 6.94 Hz, 6H), 1.51-1.68(m, 2H), 1.86 (dd, J = 13.64, 6.70 Hz, 2H), 2.58 (dt, J = 8.71, 3.29 Hz,2H), 3.36-3.40 (m, 2H), 3.69-3.85 (m, 2H), 5.82 (s, 1H), 5.92 (s, 1H),7.54 (dd, J = 8.32, 1.85 Hz, 1H), 7.63 (d, J = 1.85 Hz, 1H), 8.06 (d, J= 8.32 Hz, 1H). 217 (400 MHz, CDCl₃) 0.71 (d, J = 6.94 Hz, 3H), 0.87 (t,455 453 J = 3.24 Hz, 6H), 1.07 (d, J = 6.94 Hz, 6H), 1.51-1.68 (m, 2H),1.86 (dd, J = 13.64, 6.70 Hz, 2H), 2.58 (dt, J = 8.71, 3.29 Hz, 2H),3.36-3.40 (m, 2H), 3.69-3.85 (m, 2H), 5.82 (s, 1H), 5.92 (s, 1H), 7.54(dd, J = 8.32, 1.85 Hz, 1H), 7.63 (d, J = 1.85 Hz, 1H), 8.06 (d, J =8.32 Hz, 1H) 218 (400 MHz, CDCl₃) 0.70 (d, J = 6.70 Hz, 3H), 0.93 (d,439 437 J = 6.70 Hz, 6H), 1.04 (d, J = 6.94 Hz, 3H), 1.57 (dd, J =15.37, 6.82 Hz, 5H), 1.72-1.89 (m, 2H), 2.66 (t, J = 6.36 Hz, 2H), 2.92(t, J = 7.74 Hz, 2H), 3.76 (td, J = 6.30, 2.62 Hz, 2H), 5.24 (s, 1H),5.86 (s, 1H), 7.19 (d, J = 8.32 Hz, 1H), 7.29 (dd, J = 8.32, 2.08 Hz,1H), 7.40 (d, J = 1.85 Hz, 1H) 219 (400 MHz, CDCl₃) 0.71 (d, J = 6.94Hz, 3H), 0.99-1.08 457 455 (m, 9H), 1.83-1.90 (m, 3H), 2.18-2.28 (m,2H), 2.52- 2.60 (m, 2H), 3.28 (d, J = 6.47 Hz, 2H), 3.67-3.86 (m, 2H),5.92 (d, J = 5.32 Hz, 2H), 7.54 (dd, J = 8.44, 1.73 Hz, 1H), 7.62 (d, J= 1.85 Hz, 1H), 8.07 (d, J = 8.32 Hz, 1H) 220 (400 MHz, DMSO-D₆)0.61-0.77 (m, 3H), 0.95 (s, 483 481 9H), 0.99-1.10 (m, 3H), 1.35-1.43(m, 2H), 1.71 (s, 3H), 2.02-2.18 (m, 4H), 2.60-2.69 (m, 2H), 5.91- 6.04(m, 1H), 6.95-7.05 (m, 1H), 7.18-7.45 (m, 3H), 7.46-7.49 (m, 1H),7.62-7.67 (m, 1H), 7.67-7.75 (m, 1H) 221 (400 MHz, DMSO-D₆) 0.65-0.70(m, 3H), 0.94 (s, 499 497 9H), 1.00-1.06 (m, 3H), 1.36-1.43 (m, 2H),1.71 (s, 3H), 1.95-2.05 (m, 1H), 2.60-2.68 (m, 2H), 3.87 (s, 3H), 5.98(s, 1H), 7.29-7.36 (m, 3H), 7.37-7.44 (m, 1H), 7.52-7.60 (m, 3H), 13.03(brs, 1H) 222 (400 MHz, CDCl₃) 0.71-0.77 (m, 3H), 0.98 (s, 9H), 495 4931.03-1.10 (m, 3H), 1.40-1.49 (m, 2H), 1.71 (s, 3H), 1.87-1.97 (m, 1H),2,63-2.72 (m, 2H), 4.17-4.26 (m, 3H), 4.27-4.35 (m, 3H), 5.35 (brs, 1H),5.91 (s, 1H), 7.14-7.21 (m, 1H), 7.23-7.28 (m, 1H), 7.38- 7.41 (m, 1H)223 (400 MHz, CDCl₃) 0.66 (dd, J = 9.02, 6.94 Hz, 3H), 453 451 1.05 (dd,J = 6.82, 1.50 Hz, 3H), 1.31-2.07 (m, 20H), 2.61-2.67 (m, 2H), 3.42 (t,J = 7.86 Hz, 1H), 3.70- 3.84 (m, 2H), 5.53 (d, J = 15.95 Hz, 1H), 5.90(d, J = 3.24 Hz, 1H), 7.44 (dd, J = 17.57, 1.85 Hz, 1H), 7.54 (tt, J =13.18, 3.74 Hz, 1H), 7.78 (dd, J = 10.06, 8.21 Hz, 1H) 224 (400 MHz,CDCl₃) 0.70 (d, J = 6.94 Hz, 3H), 1.04 (d, 437 435 J = 6.94 Hz, 3H),1.54-1.89 (m, 0H), 2.10 (t, J = 7.86 Hz, 2H), 2.67 (t, J = 6.24 Hz, 2H),3.76 (t, J = 6.24 Hz, 2H), 5.19 (s, 1H), 5.87 (s, 1H), 7.28 (t, J = 2.08Hz, 2H), 7.39 (s, 1H) 225 (400 MHz, CDCl₃) 0.97 (s, 9H), 1.41-1.49 (m,2H), 485 483 1.71 (s, 3H), 2.63-2.70 (m, 2H), 3.39 (s, 3H), 3.54- 3.63(m, 3H), 3.82-3.95 (m, 1H), 5.43-5.55 (m, 1H), 6.44 (s, 1H), 6.96-7.01(m, 2H), 7.15-7.21 (m, 1H), 7.25-7.30 (m, 1H), 7.43-7.46 (m, 1H),7.83-7.87 (m, 2H) 226 (400 MHz, CDCl₃) 0.76-0.81 (m, 3H), 0.99 (s, 9H),499 497 1.10-1.14 (m, 3H), 1.42-1.49 (m, 2H), 1.82 (s, 3H), 1.95-2.04(m, 1H), 2.66-2.72 (m, 2H), 4.11 (s, 3H), 4.93 (brs, 1H), 6.23 (s, 3H),7.00-7.05 (m, 1H), 7.20- 7.25 (m, 1H), 7.29-7.34 (m, 1H), 7.36-7.40 (m,1H), 7.45-7.48 (m, 1H), 8.20-8.25 (m, 1H) 227 (400 MHz, CDCl₃) 0.70 (d,J = 6.94 Hz, 3H), 1.07 (d, 469 467 J = 6.70 Hz, 3H), 1.64 (d, J = 7.17Hz, 5H), 1.83 (dt, J = 17.42, 7.63 Hz, 4H), 2.05 (t, J = 11.33 Hz, 2H),2.57 (dd, J = 9.13, 6.59 Hz, 2H), 3.77 (ddd, J = 25.72, 13.24, 6.65 Hz,2H), 4.07 (t, J = 7.40 Hz, 1H), 5.83 (s, 1H), 5.91 (s, 1H), 7.50-7.54(m, 1H), 7.62 (d, J = 1.85 Hz, 1H), 8.06 (d, J = 8.32 Hz, 1H) 228 (400MHz, CDCl₃) 0.74 (d, J = 6.85 Hz, 3H), 0.96-1.10 447 445 (m, 4H), 0.98(s, 9H), 1.07 (d, J = 6.85 Hz, 3H), 1.46- 1.42 (m, 2H), 1.68 (s, 3H),1.87-1.93 (m, 1H), 2.64- 2.69 (m, 2H), 2.72 (s, 2H), 5.45 (s, 1H), 5.98(s, 1H), 7.18 (d, J = 8.06 Hz, 1H), 7.21 (dd, J = 8.06, 1.61 Hz, 1H),7.33 (d, J = 1.61 Hz, 1H) 229 (400 MHz, CDCl₃) 0.98 (s, 9H), 1.42-1.47(m, 2H), 495 493 1.64 (s, 3H), 1.81-1.92 (m, 2H), 2.09-2.17 (m, 1H),2.28-2.38 (m, 1H), 2.45-2.54 (m, 1H), 2.65-2.69 (m, 2H), 2.78-2.91 (m,3H), 2.94-3.04 (m, 2H), 4.66- 4.76 (m, 1H), 4.99 (s, 1H), 5.95 (s, 1H),7.21-7.17 (m, 2H), 7.34 (s, 1H) 230 (400 MHz, CDCl₃) 0.98 (s, 9H),1.14-1.19 (m, 6H), 421 419 1.40-1.48 (m, 2H), 1.67 (s, 3H), 1.99-2.11(m, 1H), 2.13-2.37 (m, 3H), 2.61-2.70 (m, 2H), 4.59-4.70 (m, 1H), 5.83(s, 1H), 5.90 (s, 1H), 7.13-7.22 (m, 2H), 7.32-7.37 (m, 1H) 231 (400MHz, MeOH-D₄) 1.01 (s, 9H), 1.44-1.51 (m, 456 454 2H), 1.84 (s, 3H),2.19-2.38 (m, 4H), 2.70-2.76 (m, 2H), 6.50 (s, 1H), 7.27-7.33 (m, 1H),7.38-7.43 (m, 1H), 7.48-7.51 (m, 1H), 7.56-7.60 (m, 2H), 8.49- 8.55 (m,2H) 232 (400 MHz, DMSO-D₆) 0.70-0.76 (m, 3H), 0.93 (s, 487 475 9H),1.03-1.07 (m, 3H), 1.32-1.41 (m, 2H), 1.57 (s, 3H), 1.91-2.26 (m, 9H),2.57-2.63 (m, 2H), 4.46- 4.59 (m, 1H), 6.15 (s, 1H), 7.01 (brs, 1H),7.19-7.23 (m, 1H), 7.25-7.32 (m, 2H) 233 (400 MHz, DMSO-D₆) 0.69-0.75.(m, 3H), 0.93 (s, 487 485 9H), 1.02-1.08 (m, 3H), 1.32-1.40 (m, 2H),1.58 (s, 3H), 1.84-2.20 (m, 9H), 2.56-2.64 (m, 2H), 4.46- 4.58 (m, 1H),6.14 (s, 1H), 7.00 (brs, 1H), 7.18-7.24 (m, 1H), 7.24-7.31 (m, 2H) 234(400 MHz, CDCl₃) 0.75 (d, J = 6.85 Hz, 3H), 0.98 (s, 461 459 9H), 1.08(d, J = 6.85 Hz, 3H), 1.42-1.46 (m, 2H), 1.71 (s, 3H), 1.74-1.89 (m,3H), 1.94-2.11 (m, 4H), 2.63- 2.68 (m, 2H), 2.80 (td, J = 8.46, 8.06 Hz,1H), 4.89 (td, J = 7.25, 8.06 Hz, 1H), 5.27 (s, 1H), 5.93 (s, 1H), 7.17(d, J = 8.06 Hz, 1H), 7.23 (dd, J = 8.06, 2.01 Hz, 1H), 7.36 (d, J =2.01 Hz, 1H) 235 (400 MHz, DMSO-D₆) 0.65 (d, J = 6.85 Hz, 3H), 0.95 475473 (s, 9H), 1.01 (d, J = 6.85 Hz, 3H), 1.22-1.46 (m, 5H), 1.55 (s, 3H),1.57-1.67 (m, 3H), 1.69-1.78 (m, 1H), 1.79-1.94 (m, 2H), 2.45-2.53 (m,1H), 2.60-2.65 (m, 2H), 4.11-4.26 (m, 1H), 6.10 (s, 1H), 6.79 (s, 1H),7.26 (dd, J = 8.06, 1.61 Hz, 1H), 7.29 (d, J = 8.06 Hz, 1H), 7.34 (d, J= 1.61 Hz, 1H) 236 (400 MHz, DMSO-D₆) 0.67-0.74 (m, 3H), 0.95 (s, 435433 9H), 1.01-1.06 (m, 3H), 1.14-1.20 (m, 3H), 1.34- 1.42 (m, 2H), 1.58(s, 3H), 1.87-1.99 (m, 1H), 2.52- 2.57 (m, 2H), 2.58-2.66 (m, 2H),4.55-4.70 (m, 1H), 6.11 (s, 1H), 6.93-6.96 (m, 1H), 7.23-7.32 (m, 2H),7.32-7.36 (m, 1H), 12.21 (brs, 1H) 237 (400 MHz, DMSO-D₆) 0.65-0.73 (m,3H), 0.95 (s, 562 560 9H), 1.02-1.07 (m, 3H), 1.35-1.40 (m, 2H), 1.42(s, 9H), 1.56-1.64 (m, 3H), 1.86-1.97 (m, 1H), 2.59- 2.66 (m, 2H),3.24-3.43 (m, 4H), 3.45-3.56 (m, 1H), 3.56-3.67 (m, 1H), 4.85-5.03 (m,1H), 6.18-6.30 (m, 1H), 7.11-7.18 (m, 1H), 7.23-7.39 (m, 3H), 12.63(brs, 1H) 238 (400 MHz, DMSO-D₆) 0.65-0.73 (m, 3H), 0.95 (s, 462 4609H), 1.02-1.08 (m, 3H), 1.35-1.42 (m, 2H), 1.59- 1.68 (m, 3H), 2.59-2.66(m, 2H), 3.25-3.52 (m, 5H), 3.58-3.68 (m, 1H), 4.77-5.03 (m, 1H),6.20-6.29 (m, 1H), 7.24-7.42 (m, 4H), 8.87-9.22 (m, 1H) 239 (400 MHz,DMSO-D₆) 0.64-0.71 (m, 3H), 0.94 (s, 504 502 9H), 1.00-1.07 (m, 3H),1.32-1.41 (m, 2H), 1.56- 1.63 (m, 3H), 1.83-1.96 (m, 4H), 2.57-2.65 (m,2H), 3.30-3.36 (m, 1H), 3.39-3.64 (m, 2H), 3.66-3.89 (m, 2H), 4.80-5.13(m, 1H), 6.13-6.32 (m, 1H), 7.10- 7.16 (m, 1H), 7.22-7.39 (m, 2H), 12.62(brs, 1H) 240 (400 MHz, DMSO-D₆) 0.65-0.72 (m, 3H), 0.93 (s, 540 5389H), 1.00-1.06 (m, 3H), 1.33-1.41 (m, 2H), 1.60 (s, 3H), 1.86-2.00 (m,1H), 2.57-2.64 (m, 2H), 2.91- 2.96 (m, 3H), 3.08-3.26 (m, 2H), 3.38-3.52(m, 2H), 3.52-3.59 (m, 1H), 4.81-5.02 (m, 1H), 6.19 (s, 1H), 7.08-7.15(m, 1H), 7.22-7.31 (m, 2H), 7.31-7.37 (m, 1H) 241 (400 MHz, DMSO-D₆)0.95 (s, 9H), 1.30-1.40 (m, 463 461 3H), 1.48-1.59 (m, 2H), 1.52 (s,3H), 2.02-2.09 (m, 2H), 2.35-2.43 (m, 3H), 2.60-2.64 (m, 2H), 3.22 (d, J= 5.64 Hz, 2H), 3.48-3.55 (m, 1H), 3.57-3.65 (m, 1H), 6.03 (s, 1H), 7.02(s, 1H), 7.22 (dd, J = 8.06, 2.01 Hz, 1H), 7.28 (d, J = 8.06 Hz, 1H),7.31 (d, J = 2.01 Hz, 1H) 242 (400 MHz, DMSO-D₆) 0.68-0.73 (m, 3H), 0.95(s, 461 459 9H), 1.02-1.07 (m, 3H), 1.33-1.42 (m, 2H), 1.47- 2.00 (m,9H), 2.53-2.57 (m, 2H), 2.58-2.66 (m, 2H), 4.67-4.78 (m, 1H), 6.04-6.08(m, 1H), 6.90-6.95 (m, 1H), 7.22-7.36 (m, 3H) 243 (400 MHz, DMSO-D₆)0.68-0.73 (m, 3H), 0.95 (s, 461 459 9H), 1.02-1.07 (m, 3H), 1.33-1.42(m, 2H), 1.47- 2.00 (m, 9H), 2.53-2.57 (m, 2H), 2.58-2.66 (m, 2H),4.67-4.78 (m, 1H), 6.04-6.08 (m, 1H), 6.90-6.95 (m, 1H), 7.22-7.36 (m,3H) 244 (400 MHz, CDCl₃) 0.85-0.89 (m, 3H), 0.97 (s, 9H), 490 4881.08-1.13 (m, 3H), 1.29-1.35 (m, 3H), 1.40-1.47 (m, 2H), 1.85 (s, 3H),2.59-2.69 (m, 2H), 3.28-3.66 (m, 5H), 3.77-3.92 (m, 1H), 4.20-4.30 (m,2H), 4.30- 4.38 (m, 1H), 5.95 (s, 1H), 7.12-7.20 (m, 1H), 7.28- 7.36 (m,1H), 7.60-7.69 (m, 1H), 8.66 (brs, 1H), 11.57 (brs, 1H) 245 (400 MHz,CDCl₃) 0.78-0.82 (m, 3H), 0.97 (s, 9H), 490 488 1.04-1.12 (m, 3H),1.22-1.35 (m, 3H), 1.38-1.52 (m, 2H), 1.80 (s, 3H), 2.57-2.72 (m, 3H),3.36-3.71 (m, 5H), 3.72-3.91 (m, 1H), 4.20-4.30 (m, 2H), 4.35- 4.47 (m,1H), 5.95 (s, 1H), 7.03-7.10 (m, 1H), 7.13- 7.20 (m, 1H), 7.23-7.26 (m,1H), 7.30-7.35 (m, 1H), 8.79 (brs, 1H), 10.94 (brs, 1H) 246 (400 MHz,DMSO-D₆) 0.95 (s, 9H), 1.35-1.40 (m, 523 521 2H), 1.53 (s, 3H),1.58-1.70 (m, 2H), 1.74-2.11 (m, 9H), 2.23-2.31 (m, 1H), 2.55 (d, J =9.27 Hz, 1H), 2.60- 2.64 (m, 2H), 2.73-2.82 (m, 1H), 4.27-4.20 (m, 1H),5.97 (s, 1H), 7.18 (s, 1H), 7.21 (dd, J = 7.86, 1.81 Hz, 1H), 7.29 (d, J= 8.06 Hz, 1H), 7.31 (d, J = 2.01 Hz, 1H) 247 (400 MHz, DMSO-D₆)0.67-0.73 (m, 3H), 0.92 (s, 435 433 9H), 1.01-1.06 (m, 3H), 1.13-1.19(m, 3H), 1.32- 1.41 (m, 2H), 1.58 (s, 3H), 1.89-2.01 (m, 1H), 2.50- 2.54(m, 2H), 2.56-2.67 (m, 2H), 4.54-4.69 (m, 1H), 6.10 (s, 1H), 6.92-6.98(m, 1H), 7.21-7.29 (m, 2H), 7.29-7.35 (m, 1H), 12.16 (brs, 1H) 248 (400MHz, CDCl₃) 0.98 (s, 9H), 1.42-1.46 (m, 2H), 509 507 1.63 (s, 3H),1.82-1.91 (m, 2H), 2.11 (q, J = 10.21 Hz, 1H), 2.29-2.55 (m, 5H),2.61-2.72 (m, 4H), 2.81- 2.90 (m, 1H), 3.63 (d, J = 7.25 Hz, 2H), 5.09(s, 1H), 5.83 (s, 1H), 7.18-7.16 (m, 2H), 7.32 (s, 1H) 249 (400 MHz,DMSO-D₆) 0.95 (s, 9H), 1.36-1.40 (m, 476 474 2H), 1.53 (s, 3H), 1.70 (t,J = 10.00 Hz, 2H), 1.89-1.96 (m, 1H), 2.18-2.25 (m, 1H), 2.29-2.35 (m,2H), 2.43- 2.53 (m, 1H), 2.60-2.75 (m, 3H), 3.49-3.56 (m, 1H), 3.58-3.66(m, 1H), 6.03 (s, 1H), 6.86 (s, 1H), 7.06 (s, 1H), 7.23 (dd, J = 1.61,8.06 Hz, 1H), 7.29 (d, J = 8.06 Hz, 1H), 7.31 (d, J = 2.01 Hz, 1H), 7.37(s, 1H) 250 (400 MHz, DMSO-D₆) 0.72-0.85 (m, 4H), 0.95 (s, 489 487 9H),1.35-1.40 (m, 2H), 1.52 (s, 3H), 1.67 (q, J = 10.21 Hz, 1H), 1.73-1.81(m, 1H), 1.91 (q, J = 10.07 Hz, 1H), 2.21-2.29 (m, 1H), 2.46-2.53 (m,1H), 2.60-2.64 (m, 2H), 2.72-2.78 (m, 1H), 3.28 (s, 3H), 3.34-3.44 (m,2H), 5.93 (s, 1H), 7.03 (s, 1H), 7.21 (dd, J = 2.01, 8.06 Hz, 1H),7.29-7.27 (m, 2H) 251 (400 MHz, CDCl₃) 0.98 (s, 9H), 1.17 (s, 3H), 1.21(s, 487 485 3H), 1.42-1.46 (m, 2H), 1.62 (s, 3H), 1.83-1.97 (m, 4H),2.10-2.18 (m, 3H), 2.28-2.36 (m, 1H), 2.44- 2.52 (m, 1H), 2.63-2.68 (m,2H), 2.80-2.89 (m, 1H), 4.79-4.88 (m, 1H), 5.27 (s, 1H), 6.06 (s, 1H),7.15 (d, J = 8.06 Hz, 1H), 7.19 (dd, J = 8.06, 1.61 Hz, 1H), 7.33 (d, J= 1.61 Hz, 1H) 252 (400 MHz, CDCl₃) 0.98 (s, 9H), 1.41-1.48 (m, 2H), 517515 1.79 (s, 3H), 1.98-2.24 (m, 2H), 2.32-2.57 (m, 2H), 2.61-2.74 (m,3H), 5.45 (brs, 1H), 6.20 (s, 1H), 7.20- 7.24 (m, 1H), 7.26-7.31 (m,1H), 7.40-7.55 (m, 3H), 8.05-8.20 (m, 2H) 253 (400 MHz, DMSO-D₆) 0.64(d, J = 6.70 Hz, 3H), 0.93 387 385 (s, 9H), 1.01 (d, J = 6.70 Hz, 3H),1.42 (dt, J = 8.55, 4.16 Hz, 2H), 1.60 (s, 3H), 1.86-1.94 (m, 1H), 2.42-2.54 (m, 4H), 3.48-3.56 (m, 1H), 3.57-3.65 (m, 1H), 6.05 (s, 1H), 6.90(s, 1H), 7.14 (d, J = 8.09 Hz, 2H), 7.28 (d, J = 8.09 Hz, 2H),12.26-12.29 (m, 1H) 254 (400 MHz, DMSO-D₆) 0.67-0.73 (m, 3H), 0.93 (s,475 473 9H), 1.00-1.06 (m, 3H), 1.32-1.54 (m, 4H), 1.55- 1.66 (m, 4H),1.70-1.81 (m, 1H), 1.83-2.02 (m, 3H), 2.56-2.63 (m, 2H), 2.74-2.80 (m,1H), 4.21-4.33 (m, 1H), 6.09 (s, 1H), 6.94 (s, 1H), 7.19-7.25 (m, 1H),7.25-7.29 (m, 1H), 7.30-7.33 (m, 1H), 12.18 (brs, 1H) 255 (400 MHz,DMSO-D₆) 0.68-0.74 (m, 3H), 0.93 (s, 475 473 9H), 1.01-1.07 (m, 3H),1.31-1.44 (m, 4H), 1.44- 1.54 (m, 2H), 1.55-1.67 (m, 4H), 1.70-1.81 (m,1H), 1.83-2.02 (m, 3H), 2.57-2.64 (m, 2H), 4.22-4.33 (m, 1H), 6.10 (s,1H), 6.94 (s, 1H), 7.19-7.24 (m, 1H), 7.24-7.29 (m, 1H), 7.29-7.33 (m,1H), 12.19 (brs, 1H) 256 (400 MHz, DMSO-D₆) 0.67-0.73 (m, 3H), 0.93 (s,475 473 9H), 1.00-1.06 (m, 3H), 1.32-1.54 (m, 4H), 1.55- 1.66 (m, 4H),1.70-1.81 (m, 1H), 1.83-2.02 (m, 3H), 2.56-2.63 (m, 2H), 2.74-2.80 (m,1H), 4.21-4.33 (m, 1H), 6.09 (s, 1H), 6.94 (s, 1H), 7.19-7.25 (m, 1H),7.25-7.29 (m, 1H), 7.30-7.33 (m, 1H), 12.18 (brs, 1H) 257 (400 MHz,DMSO-D₆) 0.68-0.74 (m, 3H), 0.93 (s, 475 473 9H), 1.01-1.07 (m, 3H),1.31-1.44 (m, 4H), 1.44- 1.54 (m, 2H), 1.55-1.67 (m, 4H), 1.70-1.81 (m,1H), 1.83-2.02 (m, 3H), 2.57-2.64 (m, 2H), 4.22-4.33 (m, 1H), 6.10 (s,1H), 6.94 (s, 1H), 7.19-7.24 (m, 1H), 7.24-7.29 (m, 1H), 7.29-7.33 (m,1H), 12.19 (brs, 1H) 258 (400 MHz, DMSO-D₆) 0.69 (d, J = 6.70 Hz, 3H),0.80 433 431 (d, J = 6.70 Hz, 6H), 1.02 (d, J = 6.70 Hz, 3H), 1.37-1.48(m, 1H), 1.60-1.69 (m, 2H), 1.60 (s, 3H), 1.83-1.97 (m, 2H), 2.38-2.48(m, 4H), 3.37-3.46 (m, 1H), 3.52 (ddd, J = 6.80, 7.20, 14.00 Hz, 1H),3.62 (ddd, J = 6.80, 7.20, 14.00 Hz, 1H), 6.11 (s, 1H), 7.03 (s, 1H),7.29- 7.34 (m, 3H), 12.30 (brs, 1H) 259 (400 MHz, CDCl₃) 0.75 (d, J =6.85 Hz, 3H), 0.98 (s, 449 447 9H), 1.04 (d, J = 6.85 Hz, 3H), 1.42-1.47(m, 2H), 1.56 (s, 3H), 1.58 (s, 3H), 1.67 (s, 3H), 1.90-1.97 (m, 1H),2.64-2.69 (m, 2H), 3.11 (d, J = 14.51 Hz, 1H), 3.19 (d, J = 14.91 Hz,1H), 4.97 (s, 1H), 6.16 (s, 1H), 7.18 (d, J = 8.06 Hz, 1H), 7.25 (dd, J= 2.01, 8.06 Hz, 1H), 7.38 (d, J = 2.01 Hz, 1H) 260 (400 MHz, CDCl₃)0.71 (d, J = 6.94 Hz, 3H), 0.98 (s, 437 435 6H), 1.05 (d, J = 6.94 Hz,3H), 1.49-1.54 (m, 2H), 1.70 (s, 3H), 1.84-1.91 (m, 1H), 2.70-2.65 (m,4H), 3.40 (s, 2H), 3.75-3.77 (m, 2H), 5.28 (s, 1H), 5.87 (s, 1H), 7.19(d, J = 8.09 Hz, 1H), 7.26 (dd, J = 8.09, 1.85 Hz, 1H), 7.38 (d, J =1.85 Hz, 1H) 261 (400 MHz, CDCl₃) 0.99 (d, J = 6.94 Hz, 3H), 1.13-1.11451 449 (m, 6H), 1.16 (s, 3H), 1.39-1.66 (m, 2H), 1.80 (s, 3H),1.91-1.96 (m, 1H), 2.14-2.23 (m, 1H), 2.53- 2.58 (m, 1H), 3.31-3.19 (m,2H), 3.96-4.00 (m, 1H), 6.12 (s, 1H), 6.66-6.69 (m, 1H), 7.13-7.16 (m,1H), 7.26 (s, 1H) 262 (400 MHz, DMSO-D₆) 0.68-0.76 (m, 3H), 0.93 (s, 489487 9H), 0.99-1.10 (m, 5H), 1.32-1.40 (m, 2H), 1.46- 1.62 (m, 7H),1.63-1.81 (m, 3H), 1.94-2.03 (m, 1H), 2.07-2.11 (m, 2H), 2.57-2.64 (m,2H), 3.99-4.10 (m, 1H), 6.13 (s, 1H), 6.97 (brs, 1H), 7.20-7.29 (m, 2H),7.29-7.33 (m, 1H) 263 (400 MHz, CDCl₃) 0.69 (d, J = 6.85 Hz, 3H), 1.05(d, 419 417 J = 6.85 Hz, 3H), 1.17-1.26 (m, 2H), 1.50-1.56 (m, 2H),1.62-1.68 (m, 4H), 1.70 (s, 3H), 1.84-1.91 (m, 1H), 2.13-2.21 (m, 1H),2.66 (t, J = 6.25 Hz, 2H), 2.71 (d, J = 7.25 Hz, 2H), 3.70-3.84 (m, 2H),5.28 (s, 1H), 5.86 (s, 1H), 7.17 (d, J = 8.06 Hz, 1H), 7.26-7.24 (m,1H), 7.38 (d, J = 2.01 Hz, 1H) 264 (400 MHz, CDCl₃) 0.71 (d, J = 6.85Hz, 3H), 1.05 (d, 417 415 J = 6.85 Hz, 3H), 1.68-1.77 (m, 4H), 1.71 (s,3H), 1.85- 1.92 (m, 1H), 2.45 (t, J = 7.05 Hz, 2H), 2.53 (t, J = 6.85Hz, 2H), 2.67 (t, J = 6.25 Hz, 2H), 3.84-3.71 (m, 2H), 5.30 (s, 1H),5.87 (s, 1H), 6.55 (t, J = 2.01 Hz, 1H), 7.29 (dd, J = 8.06, 2.42 Hz,1H), 7.39 (d, J = 8.87 Hz, 1H), 7.41 (d, J = 2.01 Hz, 1H) 265 (400 MHz,CDCl₃) 0.98 (s, 9H), 1.44-1.48 (m, 2H), 455 453 1.67 (s, 3H), 2.65-2.70(m, 2H), 2.72 (t, J = 6.04 Hz, 2H), 3.91-3.75 (m, 2H), 5.49 (s, 1H),6.25 (s, 1H), 6.87 (dd, J = 8.06, 1.61 Hz, 2H), 7.25-7.14 (m, 5H), 7.38(d, J = 2.01 Hz, 1H) 266 (400 MHz, DMSO-D₆) 0.69-0.76 (m, 3H), 0.94 (s,483 481 9H), 1.04-1.10 (m, 3H), 1.34-1.42 (m, 2H), 1.70 (s, 3H),1.96-2.09 (m, 1H), 2.43-2.53 (m, 3.H), 2.60- 2.67 (m, 2H), 6.29 (s, 1H),7.06-7.18 (m, 2H), 7.29- 7.39 (m, 2H), 7.40-7.46 (m, 2H), 7.64-7.75 (m,1H) 267 (400 MHz, CDCl₃) 0.71 (d, J = 6.85 Hz, 3H), 1.05 (d, 431 429 J =6.85 Hz, 3H), 1.54-1.69 (m, 6H), 1.71 (s, 3H), 1.86- 1.93 (m, 1H), 2.22(t, J = 5.64 Hz, 2H), 2.30 (t, J = 5.64 Hz, 2H), 2.65 (t, J = 6.25 Hz,2H), 3.71-3.82 (m, 2H), 5.45 (s, 1H), 5.88 (s, 1H), 6.18 (s, 1H), 7.18(d, J = 8.06 Hz, 1H), 7.28 (dd, J = 8.06, 1.61 Hz, 1H), 7.41 (d, J =1.61 Hz, 1H) 268 (400 MHz, CDCl₃) 0.69 (d, J = 6.85 Hz, 3H), 0.95-0.98433 431 (m, 2H), 1.04 (d, J = 6.85 Hz, 3H), 1.13-1.22 (m, 3H), 1.60-1.68(m, 6H), 1.70 (s, 3H), 1.84-1.91 (m, 1H), 2.58 (d, J = 6.85 Hz, 2H),2.64 (t, J = 6.45 Hz, 2H), 3.83- 3.70 (m, 2H), 5.49 (s, 1H), 5.86 (s,1H), 7.12 (d, J = 8.06 Hz, 1H), 7.24 (dd, J = 8.06, 2.01 Hz, 1H), 7.38(d, J = 2.01 Hz, 1H) 269 (400 MHz, DMSO-D₆) 0.68-0.74 (m, 3H), 0.94 (s,487 485 9H), 1.00-1.06 (m, 3H), 1.31-1.46 (m, 4H), 1.46- 1.53 (m, 2H),1.57 (s, 3H), 1.71-1.81 (m, 2H), 1.81- 1.91 (m, 2H), 1.99-2.05 (m, 1H),2.08-2.19 (m, 2H), 2.56-2.64 (m, 2H), 6.09 (s, 1H), 6.80 (brs, 1H),7.20- 7.31 (m, 2H), 7.31-7.37 (m, 1H) 270 (400 MHz, DMSO-D₆) 0.62-0.69(m, 3H), 0.93 (s, 455 453 9H), 0.99-1.05 (m, 3H), 1.36-1.43 (m, 2H),1.63 (s, 3H), 1.84-1.94 (m, 1H), 2.39-2.45 (m, 2H), 2.62- 2.69 (m, 2H),3.45-3.54 (m, 1H), 3.57-3.67 (m, 1H), 6.13 (s, 1H), 7.07 (s, 1H),7.38-7.43 (m, 1H), 7.54- 7.61 (m, 2H), 12.28 (brs, 1H) 271 (400 MHz,DMSO-D₆) 0.70-0.74 (m, 3H), 0.93 (s, 503 501 9H), 1.06-1.12 (m, 3H),1.36-1.44 (m, 2H), 1.75 (s, 3H), 1.98-2.08 (m, 1H), 2.63-2.72 (m, 2H),6.42 (s, 1H), 7.42-7.50 (m, 3H), 7.60-7.63 (m, 1H), 7.65- 7.70 (m, 2H),7.90-7.96 (m, 2H), 12.89 (brs, 1H) 272 (400 MHz, DMSO-D₆) 0.67-0.73 (m,3H), 0.95 (s, 473 471 9H), 1.01-1.06 (m, 3H), 1.34-1.43 (m, 2H), 1.60(s, 3H), 1.62-1.84 (m, 8H), 1.95-2.06 (m, 1H), 2.59- 2.66 (m, 2H), 5.91(s, 1H), 6.90 (brs, 1H), 7.22-7.37 (m, 3H) 273 (400 MHz, CDCl₃) 0.98 (s,9H), 1.44-1.48 (m, 2H), 485 483 1.71 (s, 3H), 2.66-2.71 (m, 2H), 3.41(s, 3H), 3.57- 3.61 (m, 3H), 3.88-3.94 (m, 1H), 5.46 (s, 1H), 6.35 (s,1H), 7.01 (dt, J = 8.46, 2.01 Hz, 1H), 7.19-7.30 (m, 3H), 7.45 (d, J =2.01 Hz, 1H), 7.74 (t, J = 1.61 Hz, 1H), 7.90 (dt, J = 7.66, 1.41 Hz,1H) 274 (400 MHz, DMSO-D₆) 0.94 (s, 9H), 1.32-1.41 (m, 489 487 2H), 1.55(s, 3H), 1.73-1.84 (m, 6H), 1.85-1.89 (m, 2H), 1.90-1.99 (m, 1H),2.01-2.12 (m, 1H), 2.57- 2.64 (m, 2H), 3.10 (s, 3H), 3.11-3.25 (m, 2H),5.93 (s, 1H), 7.04 (brs, 1H), 7.22-7.27 (m, 1H), 7.27-7.32 (m, 1H),7.32-7.36 (m, 1H), 12.30 (brs, 1H) 275 (400 MHz, DMSO-D₆) 0.95 (s, 9H),1.38-1.43 (m, 486 484 2H), 1.62 (s, 3H), 2.64-2.68 (m, 2H), 3.28 (s,3H), 3.41-3.53 (m, 3H), 3.80-3.87 (m, 1H), 6.79 (s, 1H), 7.34 (dd, J =8.06, 1.61 Hz, 1H), 7.37 (d, J = 8.46 Hz, 1H), 7.47 (d, J = 1.21 Hz,1H), 7.54 (s, 1H), 7.71 (t, J = 2.22 Hz, 1H), 8.39 (d, J = 1.61 Hz, 1H),8.85 (d, J = 1.21 Hz, 1H) 276 (400 MHz, CDCl₃) 0.97 (s, 9H), 1.39-1.48(m, 2H), 511 509 1.71-1.84 (m, 5H), 2.07-2.23 (m, 2H), 2.63-2.71 (m,2H), 2.83-2.96 (m, 1H), 3.17 (s, 3H), 3.76-3.85 (m, 1H), 5.45 (brs, 1H),6.19-6.22 (m, 1H), 7.16- 7.22 (m, 1H), 7.23-7.29 (m, 1H), 7.38-7.44 (m,1H), 7.46-7.53 (m, 2H), 8.08-8.16 (m, 2H) 277 (400 MHz, CDCl₃) 0.98 (s,9H), 1.41-1.48 (m, 2H), 511 509 1.48-1.58 (m, 1H), 1.72-1.81 (m, 4H),1.90-2.00 (m, 1H), 2.01-2.13 (m, 1H), 2.39-2.49 (m, 1H), 2.63- 2.71 (m,2H), 3.16 (s, 3H), 3.52-3.64 (m, 1H), 5.33 (s, 1H), 6.17-6.21 (m, 1H),7.18-7.23 (m, 1H), 7.26- 7.31 (m, 1H), 7.40-7.43 (m, 1H), 7.47-7.52 (m,2H), 8.07-8.14 (m, 2H) 278 (400 MHz, DMSO-D₆) 0.70-0.75 (m, 3H), 0.93(s, 461 459 9H), 1.01-1.07 (m, 3H), 1.32-1.41 (m, 2H), 1.51- 1.66 (m,4H), 1.66-1.92 (m, 4H), 1.92-2.05 (m, 2H), 2.57-2.64 (m, 2H), 2.69-2.80(m, 1H), 4.65-4.77 (m, 1H), 6.18 (s, 1H), 7.03 (brs, 1H), 7.19-7.26 (m,1H), 7.25-7.34 (m, 2H), 12.17 (brs, 1H) 279 (400 MHz, DMSO-D₆) 0.67-0.74(m, 3H), 0.93 (s, 461 459 9H), 1.01-1.09 (m, 3H), 1.30-1.41 (m, 2H),1.53- 1.64 (m, 4H), 1.67-1.93 (m, 4H), 1.93-2.05 (m, 2H), 2.56-2.64 (m,2H), 2.69-2.81 (m, 1H), 4.65-4.78 (m, 1H), 6.19 (s, 1H), 7.02 (s, 1H),7.19-7.34 (m, 3H), 12.20 (brs, 1H) 280 (400 MHz, CDCl₃) 0.71-0.78 (m,3H), 0.97 (s, 9H), 461 459 1.03-1.10 (m, 3H), 1.40-1.49 (m, 2H),1.64-1.76 (m, 4H), 1.81-1.99 (m, 3H), 2.04-2.16 (m, 2H), 2.23- 2.34 (m,1H), 2.61-2.71 (m, 2H), 2.91-3.03 (m, 1H), 4.82-4.96 (m, 1H), 5.63 (brs,1H), 5.86 (brs, 1H), 7.14-7.19 (m, 1H), 7.20-7.25 (m, 1H), 7.34- 7.38(m, 1H) 281 (400 MHz, DMSO-D₆) 0.76 (d, J = 6.85 Hz, 3H), 0.95 470 468(s, 9H), 1.12 (d, J = 6.85 Hz, 3H), 1.36-1.40 (m, 2H), 1.74 (s, 3H),2.06-2.13 (m, 1H), 2.62-2.66 (m, 2H), 7.29 (s, 1H), 7.32-7.36 (m, 2H),7.41 (s, 1H), 7.91 (s, 1H), 8.06 (dd, J = 8.87, 0.81 Hz, 1H), 8.22 (dd,J = 8.87, 2.42 Hz, 1H), 8.90 (dd, J = 2.42, 0.81 Hz, 1H), 13.20 (s, 1H)282 (400 MHz, CDCl₃) 0.68 (d, J = 6.85 Hz, 3H), 1.05 (d, 441 439 J =6.85 Hz, 3H), 1.71 (s, 3H), 1.83-1.90 (m, 1H), 2.22- 2.34 (m, 2H),2.47-2.56 (m, 1H), 2.58-2.69 (m, 4H), 2.90 (d, J = 7.66 Hz, 2H),3.82-3.70 (m, 2H), 5.68 (s, 1H), 5.87 (s, 1H), 7.13 (d, J = 8.06 Hz,1H), 7.29 (dd, J = 8.06, 2.01 Hz, 1H), 7.42 (d, J = 2.01 Hz, 1H) 283(400 MHz, DMSO-D₆) 0.69-0.75 (m, 3H), 0.94 (s, 537 535 9H), 1.05-1.10(m, 3H), 1.34-1.42 (m, 2H), 1.71 (s, 3H), 1.97-2.08 (m, 1H), 2.59-2.68(m, 2H), 6.38 (s, 1H), 7.30-7.39 (m, 2H), 7.42-7.45 (m, 1H), 7.46- 7.72(m, 4H) 284 (400 MHz, DMSO-D₆) 0.69 (d, J = 12.49 Hz, 1H), 0.80 519 517(s, 3H), 0.91 (s, 3H), 0.94 (s, 9H), 1.07 (s, 3H), 1.09- 1.23 (m, 2H),1.12 (s, 3H), 1.32-1.37 (m, 2H), 1.53 (d, J = 12.09 Hz, 1H), 1.61 (s,3H), 1.99-2.06 (m, 1H), 2.44 (t, J = 6.85 Hz, 2H), 2.61-2.65 (m, 2H),3.51- 3.62 (m, 2H), 6.06 (s, 1H), 7.09 (s, 1H), 7.29 (d, J = 8.06 Hz,1H), 7.32 (dd, J = 8.06, 1.61 Hz, 1H), 7.40 (d, J = 1.61 Hz, 1H) 285(400 MHz, CDCl₃) 0.70 (d, J = 6.85 Hz, 3H), 0.98 (s, 459 457 6H), 1.04(d, J = 6.85 Hz, 3H), 1.34 (t, J = 6.25 Hz, 2H), 1.46 (t, J = 6.25 Hz,2H), 1.69 (s, 3H), 1.85-1.92 (m, 1H), 2.24 (t, J = 6.04 Hz, 2H), 2.32(t, J = 6.04 Hz, 2H), 2.63 (t, J = 6.45 Hz, 2H), 3.68-3.82 (m, 2H), 5.80(s, 1H), 5.87 (s, 1H), 6.19 (s, 1H), 7.18 (d, J = 8.06 Hz, 1H), 7.27(dd, J = 8.06, 2.01 Hz, 1H), 7.40 (d, J = 2.01 Hz, 1H) 286 (400 MHz,CDCl₃) 0.68 (d, J = 6.85 Hz, 3H), 0.87 (s, 461 459 3H), 0.88 (s, 3H),1.03 (d, J = 6.85 Hz, 3H), 1.08-1.23 (m, 4H), 1.33-1.36 (m, 2H),1.45-1.56 (m, 3H), 1.68 (s, 3H), 1.83-1.90 (m, 1H), 2.60-2.63 (m, 4H),3.67- 3.82 (m, 2H), 5.85 (s, 1H), 5.86 (s, 1H), 7.12 (d, J = 8.06 Hz,1H), 7.24 (dd, J = 8.06, 2.01 Hz, 1H), 7.37 (d, J = 2.01 Hz, 1H) 287(400 MHz, DMSO-D₆) 0.93 (s, 9H), 1.02 (d, 487 485 J = 6.24 Hz, 1H),1.12, (s, 3H), 1.14 (s, 3H), 1.22 (s, 1H), 1.34-1.38 (m, 2H), 1.48 (s,3H), 1.83-1.85 (m, 2H), 1.89-2.05 (m, 4H), 2.22-2.25 (m, 1H), 2.59- 2.63(m, 2H), 2.79 (t, J = 8.55 Hz, 1H), 3.52 (brs, 1H), 4.65-4.74 (m, 1H),6.15 (s, 1H), 7.07 (s, 1H), 7.14- 7.16 (m, 1H), 7.25-7.26 (m, 2H) 288(400 MHz, CDCl₃) 0.71 (d, J = 6.85 Hz, 3H), 1.04 (d, 403 401 J = 6.85Hz, 3H), 1.70 (s, 3H), 1.84-1.91 (m, 1H), 2.08- 2.17 (m, 2H), 2.67 (t, J= 6.25 Hz, 2H), 2.92 (t, J = 7.66 Hz, 2H), 2.99 (t, J = 8.06 Hz, 2H),3.71-3.83 (m, 2H), 5.28 (s, 1H), 5.87 (s, 1H), 6.41 (t, J = 2.22 Hz,1H), 7.26-7.27 (m, 2H), 7.40 (d, J = 1.21 Hz, 1H) 289 (400 MHz, CDCl₃)0.72 (d, J = 6.85 Hz, 3H), 1.06 (d, 433 431 J = 6.85 Hz, 3H), 1.72 (s,3H), 1.93-1.87 (m, 1H), 2.37 (t, J = 5.04 Hz, 2H), 2.44 (t, J = 5.04 Hz,2H), 2.66 (t, J = 6.25 Hz, 2H), 3.67 (t, J = 5.44 Hz, 2H), 3.75-3.82 (m,4H), 5.34 (s, 1H), 5.89 (s, 1H), 6.30 (s, 1H), 7.17 (d, J = 8.06 Hz,1H), 7.29 (dd, J = 8.46, 2.42 Hz, 1H), 7.44 (d, J = 2.01 Hz, 1H) 290(400 MHz, CDCl₃) 0.69 (d, J = 6.85 Hz, 3H), 1.05 (d, 435 433 J = 6.85Hz, 3H), 1.33-1.43 (m, 2H), 1.50-1.54 (m, 2H), 1.71. (s, 3H), 1.81-1.91(m, 2H), 2.61-2.67 (m, 4H) 3.33 (td, J = 11.69, 1.61 Hz, 2H), 3.76 (dt,J = 20.42, 7.25 Hz, 2H), 3.94 (dd, J = 11.28, 2.82 Hz, 2H), 5.56 (s,1H), 5.87 (s, 1H), 7.13 (d, J = 8.06 Hz, 1H), 7.27 (dd, J = 8.06, 2.01Hz, 1H), 7.41 (d, J = 2.01 Hz, 1H) 291 (400 MHz, CDCl₃) 0.68 (d, J =6.85 Hz, 3H), 1.04 (d, 405 403 J = 6.85 Hz, 3H), 1.69 (s, 3H), 1.71-1.77(m, 2H), 1.81- 1.90 (m, 3H), 1.99-2.08 (m, 2H), 2.60-2.68 (m, 3H), 2.80(d, J = 7.66 Hz, 2H), 3.70-3.83 (m, 2H), 5.32 (s, 1H), 5.86 (s, 1H),7.12 (d, J = 8.06 Hz, 1H), 7.24 (dd, J = 8.06, 2.01 Hz, 1H), 7.38 (d, J= 2.01 Hz, 1H) 292 (400 MHz, CDCl₃) 0.96 (s, 12H), 1.40-1.45 (m, 2H),419 417 1.66 (s, 3H), 1.80 (s, 3H), 2.61-2.71 (m, 4H), 3.69- 3.87 (m,2H), 4.45 (s, 1H), 4.69 (s, 1H), 5.23 (s, 1H), 6.24 (s, 1H), 7.14 (d, J= 7.86 Hz, 1H), 7.22 (dd, J = 7.86, 1.62 Hz, 1H), 7.36 (d, J = 1.62 Hz,1H) 293 (400 MHz, CDCl₃) 0.71 (d, J = 6.88 Hz, 3H), 1.05 (d, 423 421 J =6.88 Hz, 3H), 1.26 (s, 1H), 1.30 (s, 6H), 1.70 (s, 3H), 1.71-1.76 (m,2H), 1.85-1.92 (m, 1H), 2.59- 2.72 (m, 2H), 2.76-2.81 (m, 2H), 3.69-3.82(m, 2H), 5.46 (s, 1H), 5.87 (s, 1H), 7.19 (d, J = 8.07 Hz, 1H), 7.26(dd, J = 8.07, 2.09 Hz, 1H), 7.38 (d, J = 2.09 Hz, 1H) 294 (400 MHz,CDCl₃) 0.70 (d, J = 6.88 Hz, 3H), 1.05 (d, 425 423 J = 6.88 Hz, 3H),1.40 (s, 3H), 1.46 (s, 3H), 1.71 (s, 3H), 1.84-1.93 (m, 3H), 2.66 (t, J= 6.28 Hz, 2H), 2.79- 2.84 (m, 2H), 3.71-3.84 (m, 2H), 5.40 (brs, 1H),5.88 (s, 1H), 7.20 (d, J = 8.07 Hz, 1H), 7.28 (dd, J = 8.07, 2.09 Hz,1H), 7.40 (d, J = 1.79 Hz, 1H) 295 (400 MHz, DMSO-D₆) 0.73 (d, J = 6.82Hz, 3H), 0.95 460 458 (s, 9H), 1.10 (d, J = 6.82 Hz, 3H), 1.35-1.41 (m,2H), 1.73 (s, 3H), 2.02-2.10 (m, 1H), 2.61-2.67 (m, 2H), 6.79 (s, 1H),7.30-7.41 (m, 4H), 8.01 (s, 1H) 296 (400 MHz, CDCl₃) 0.98 (s, 9H),1.41-1.46 (m, 2H), 517 515 1.66 (s, 6H), 1.67 (s, 3H), 2.66-2.71 (m,2H), 3.39 (s, 3H), 3.56-3.65 (m, 3H), 3.74-3.81 (m, 1H), 5.15 (s, 1H),6.23 (s, 1H), 6.80 (s, 1H), 7.09 (s, 1H), 7.19 (d, J = 8.06 Hz, 1H),7.28 (dd, J = 8.06, 2.01 Hz, 1H), 7.43 (d, J = 1.61 Hz, 1H) 297 (400MHz, DMSO-D₆) 0.70 (d, J = 6.90 Hz, 3H), 0.94 473 471 (s, 9H), 1.05 (d,J = 6.90 Hz, 3H), 1.36-1.41 (m, 2H), 1.71 (s, 3H), 2.61-2.66 (m, 2H),3.55 (s, 3H), 6.11 (s, 1H), 6.32 (brs, 1H), 7.35 (brs, 2H), 7.43 (brs,1H), 7.67 (brs, 1H) 298 (400 MHz, CDCl₃) 0.72 (d, J = 6.94 Hz, 3H), 1.05(d, 419 417 J = 6.94 Hz, 3H), 1.10 (s, 3H), 1.28 (s, 3H), 1.70 (s, 3H),1.85-1.92 (m,, 3H), 2.21-2.26 (m, 2H), 2.69 (t, J = 6.24 Hz, 2H),3.66-3.83 (m, 3H), 5.20 (brs, 1H), 5.88 (s, 1H), 7.25 (d, J = 8.21 Hz,1H), 7.30 (dd, J = 8.21, 2.08 Hz, 1H), 7.36 (d, J = 2.08 Hz, 1H) 299(400 MHz, CDCl₃) 0.61-0.71 (m, 3H), 0.95 (s, 9H), 435 433 0.99-1.06 (m,3H), 1.11-1.17 (m, 3H), 1.38-1.47 (m, 2H), 1.67 (brs, 3H), 1.78-1.90 (m,1H), 2.59- 2.67 (m, 2H), 2.72-2.85 (m, 1H), 3.46-3.60 (m, 1H), 3.62-3.75(m, 1H), 5.76-5.85 (m, 2H), 7.11-7.17 (m, 1H), 7.21-7.25 (m, 1H),7.33-7.38 (m, 1H) 300 (400 MHz, CDCl₃) 0.61-0.71 (m, 3H), 0.95 (s, 9H),435 433 0.99-1.06 (m, 3H), 1.11-1.17 (m, 3H), 1.38-1.47 (m, 2H), 1.67(brs, 3H), 1.78-1.90 (m, 1H), 2.59- 2.67 (m, 2H), 2.72-2.85 (m, 1H),3.46-3.60 (m, 1H), 3.62-3.75 (m, 1H), 5.76-5.85 (m, 2H), 7.11-7.17 (m,1H), 7.21-7.25 (m, 1H), 7.33-7.38 (m, 1H) 301 (400 MHz, CDCl₃) 0.71 (d,J = 6.94 Hz, 3H), 1.05 (d, 451 449 J = 6.94 Hz, 3H), 1.58-1.67 (m, 4H),1.71 (s, 3H), 1.80- 1.91 (m, 3H), 1.94-2.04 (m, 4H), 2.68 (t, J = 6.24Hz, 2H), 2.86-2.90 (m, 2H), 3.72-3.83 (m, 2H), 5.24 (s, 1H), 5.88 (s,1H), 7.21 (d, J = 8.09 Hz, 1H), 7.27 (dd, J = 8.09, 2.08 Hz, 1H), 7.40(d, J = 2.08 Hz, 1H) 302 (400 MHz, DMSO-D₆) 0.65-0.71 (m, 3H), 0.79 (s,447 445 9H), 0.99-1.03 (m, 3H), 1.58 (s, 3H), 1.68-1.81 (m, 2H),1.87-1.97 (m, 1H), 2.04-2.15 (m, 1H), 2.17- 2.33 (m, 4H), 3.30-3.40 (m,1H), 3.40-3.50 (m, 1H), 3.51-3.61 (m, 1H), 6.10 (s, 1H), 6.91 (brs, 1H),7.27- 7.32 (m, 3H) 303 (400 MHz, DMSO-D₆) 1.03 (s, 9H), 1.36-1.41 (m,485 483 2H), 1.61 (s, 3H), 2.03-2.11 (m, 1H), 2.21.-2.29 (m, 1H), 2.46(t, J = 7.17 Hz, 2H), 2.61-2.65 (m, 2H), 2.92 (s, 3H), 2.93-2.98 (m,1H), 3.15-3.22 (m, 1H), 3.48- 3.65 (m, 2H), 6.16 (s, 1H), 7.20 (s, 1H),7.26 (dd, J = 8.09, 1.85 Hz, 1H), 7.31 (d, J = 8.09 Hz, 1H), 7.37 (d, J= 1.85 Hz, 1H), 12.26 (brs, 1H) 304 (400 MHz, CDCl₃) 0.83 (s, 9H),0.96-1.03 (m, 3H), 477 475 1.65-1.69 (m, 3H), 1.70-1.84 (m, 3H),1.91-2.06 (m, 1H), 2.08-2.21 (m, 1H), 2.24-2.36 (m, 2H), 2.58- 2.66 (m,2H), 2.89-3.05 (m, 1H), 3.14-3.18 (m, 3H), 3.35-3.48 (m, 1H), 3.66-3.88(m, 2H), 5.66- 5.72 (m, 1H), 5.93-5.99 (m, 1H), 7.20-7.24 (m, 1H),7.27-7.32 (m, 1H), 7.35-7.38 (m, 1H) 305 (400 MHz, DMSO-D₆) 0.69 (d, J =6.94 Hz, 3H), 0.95 451 449 (s, 9H), 1.35-1.41 (m, 2H), 1.58 (s, 3H),1.90-2.00 (m, 1H), 2.45 (t, J = 6.94 Hz, 2H), 2.60-2.66 (m, 2H), 3.08(t, J = 9.02 Hz, 1H), 3.21 (s, 3H), 3.46-3.65 (m, 2H), 6.11 (s, 1H),7.07 (s, 1H), 7.25-7.31 (m, 2H), 7.33-7.36 (m, 1H) 306 (400 MHz,DMSO-D₆) 0.95 (s, 9H), 1.02 (d, 451 449 J = 6.94 Hz, 3H), 1.34-1.40 (m,2H), 1.60 (s, 3H), 1.93- 2.02 (m, 1H), 2.42 (t, J = 7.05 Hz, 2H),2.56-2.66 (m, 3H), 2.85 (t, J = 9.36 Hz, 1H), 2.90 (s, 3H), 3.48-3.63(m, 2H), 6.08 (s, 1H), 7.05 (s, 1H), 7.26-7.31 (m, 2H), 7.36 (s, 1H) 307(400 MHz, DMSO-D₆) 0.73 (d, J = 6.94 Hz, 3H), 0.95 499 497 (s, 9H),1.37-1.43 (m, 2H), 1.69 (s, 3H), 2.05-2.11 (m, 1H), 2.63-2.68 (m, 2H),3.19 (t, J = 8.90 Hz, 1H), 3.23 (s, 3H), 3.33-3.37 (m, 2H), 6.30 (s,1H), 7.17 (d, J = 8.32 Hz, 2H), 7.33-7.46 (m, 4H), 7.83 (d, J = 8.32 Hz,2H) 308 (400 MHz, DMSO-D₆) 0.95 (s, 9H), 1.09 (d, 499 497 J = 6.70 Hz,3H), 1.36-1.41 (m, 2H), 1.73 (s, 3H), 2.08- 2.14 (m, 1H), 2.62-2.71 (m,3H), 2.92 (s, 3H), 2.96 (t, J = 9.13 Hz, 1H), 6.37 (s, 1H), 7.33-7.48(m, 5H), 7.58 (s, 1H), 7.91-7.94 (m, 2H) 309 (400 MHz, DMSO-D₆) 0.69 (d,J = 6.82 Hz, 3H), 0.87 461 459 (s, 9H), 1.02 (d, J = 6.82 Hz, 3H), 1.32(d, J = 6.70 Hz, 2H), 1.60 (s, 3H), 1.65 (d, J = 32.60 Hz, 2H), 1.93(sep, J = 6.82 Hz, 1H), 2.28-2.40 (m, 1H), 2.43-2.46 (m, 2H), 2.48-2.54(m, 2H), 3.44-3.56 (m, 2H), 3.62 (ddd, J = 6.80, 7.20, 14.00 Hz, 1H),6.11 (s, 1H), 7.01 (s, 1H), 7.29-7.33 (m, 3H), 12.32 (brs, 1H) 310 (400MHz, DMSO-D₆) 0.73 (d, J = 6.82 Hz, 3H), 0.91 437 435 (s, 9H), 1.04 (d,J = 6.82 Hz, 3H), 1.61 (s, 3H), 1.93- 2.00 (m, 1H), 2.36-2.46 (m, 3H),2.93-2.98 (m, 1H), 3.47-3.55 (m, 1H), 3.58-3.66 (m, 1H), 4.38 (brs, 1H),6.12 (s, 1H), 7.01 (s, 1H), 7.24 (dd, J = 7.98, 1.97 Hz, 1H), 7.31-7.34(m, 2H) 311 (400 MHz, DMSO-D₆) 0.73 (d, J = 6.82 Hz, 3H), 0.91 437 435(s, 9H), 1.04 (d, J = 6.82 Hz, 3H), 1.61 (s, 3H), 1.92- 2.00 (m, 1H),2.36-2.45 (m, 3H), 2.96 (dd, J = 13.76, 1.50 Hz, 1H), 3.47-3.55 (m, 1H),3.58-3.66 (m, 1H), 4.39 (brs, 1H), 6.12 (s, 1H), 7.00 (s, 1H), 7.24 (dd,J = 8.09, 1.85 Hz, 1H), 7.31-7.35 (m, 2H) 312 (400 MHz, CDCl₃) 0.97 (s,9H), 1.39-1.47 (m, 2H), 503 501 1.52-1.68 (m, 5H), 2.07-2.26 (m, 2H),2.36-2.47 (m, 1H), 2.56-2.68 (m, 6H), 2.98-3.08 (m, 1H), 3.46- 3.51 (m,2H), 3.72 (s, 3H), 4.64-4.69 (m, 1H), 4.89- 5.01 (m, 1H), 5.90-5.94 (m,1H), 7.12-7.21 (m, 2H), 7.32-7.35 (m, 1H) 313 (400 MHz, CDCl₃) 0.98 (s,9H), 1.12 (s, 9H), 1.37- 541 539 1.74 (m, 6H), 1.80 (s, 3H), 2.65-2.73(m, 2H), 3.19- 3.29 (m, 2H), 5.15 (s, 1H), 6.18 (s, 1H), 7.19-7.33 (m,2H), 7.42-7.52 (m, 3H), 8.07-8.13 (m, 2H) 314 (400 MHz, DMSO-D₆)0.66-0.71 (m, 3H), 0.94 (s, 507 505 9H), 1.02-1.07 (m, 3H), 1.37-1.44(m, 2H), 1.65 (s, 3H), 1.78-1.82 (m, 2H), 1.81-1.87 (m, 4H), 1.91- 1.96(m, 2H), 1.96-2.05 (m, 1H), 2.64-2.71 (m, 2H), 5.96 (s, 1H), 7.04 (s,1H), 7.40-7.47 (m, 1H), 7.56- 7.63 (m, 2H), 12.27 (brs, 1H) 315 (400MHz, DMSO-D₆) 0.79 (s, 9H), 1.68 (s, 3H), 1.70- 511 509 1.81 (m, 2H),1.96-2.08 (m, 1H), 2.08-2.17 (m, 2H), 2.17-2.28 (m, 2H), 3.11 (s, 3H),3.16-3.44 (m, 3H), 6.38 (s, 1H), 7.32-7.48 (m, 5H), 7.61-7.65 (m, 1H),7.89-7.96 (m, 2H), 12.86 (brs, 1H) 316 (400 MHz, DMSO-D₆) 0.93 (s, 9H),1.33-1.40 (m, 507 505 2H), 1.54 (brs, 3H), 2.15 (brs, 6H), 2.17-2.27 (m,2H), 2.38-2.46 (m, 2H), 2.58-2.64 (m, 2H), 2.65- 2.77 (m, 1H), 6.01(brs, 1H), 7.14 (brs, 1H), 7.18- 7.24 (m, 1H), 7.27-7.33 (m, 2H) 317(400 MHz, DMSO-D₆) 0.66 (d, J = 6.94 Hz, 3H), 1.02 417 415 (d, J = 6.94Hz, 3H), 1.30 (s, 9H), 1.61 (s, 3H), 1.89- 1.95 (m, 1H), 2.45 (t, J =6.94 Hz, 2H), 3.48-3.67 (m, 2H), 6.12 (s, 1H), 7.10 (s, 1H), 7.31 (dd, J= 8.09, 1.85 Hz, 1H), 7.43 (d, J = 8.09 Hz, 1H), 7.43 (d, J = 1.85 Hz,1H), 12.25 (brs, 1H) 318 (400 MHz, DMSO-D₆) 0.81 (d, J = 6.70 Hz, 6H),1.38- 497 495 1.49 (m, 1H), 1.63-1.69 (m, 2H), 1.69 (s, 3H), 1.84- 1.96(m, 1H), 1.99-2.08 (m, 1H), 2.13-2.23 (m, 1H), 2.40-2.48 (m, 2H), 3.13(s, 3H), 3.20-3.29 (m, 2H), 3.44 (tt, J = 9.66, 7.33 Hz, 1H), 6.39 (s,1H), 7.35-7.44 (m, 3H), 7.46 (dt, J = 8.94, 2.20 Hz, 2H), 7.65 (s, 1H),7.94 (dt, J = 8.94, 2.20 Hz, 2H), 12.91 (brs, 1H) 319 (400 MHz, CDCl₃)0.96 (s, 9H), 1.40-1.46 (m, 2H), 469 467 1.89-2.16 (m, 3H), 2.26-2.45(m, 2H), 2.56-2.70 (m, 4H), 3.69-3.78 (m, 1H), 3.78-3.88 (m, 1H), 5.65(brs, 1H), 5.89-5.93 (m, 1H), 7.13-7.22 (m, 2H), 7.33-7.36 (m, 1H) 320(400 MHz, DMSO-D₆) 0.94 (s, 9H), 1.33-1.41 (m, 518 516 2H), 1.69 (s,3H), 2.14-2.36 (m, 2H), 2.56-2.67 (m, 3H), 2.75-2.90 (m, 1H), 3.23-3.44(m, 1H), 7.23- 7.35 (m, 3H), 7.39-7.42 (m, 1H), 7.97-8.03 (m, 2H),8.19-8.25 (m, 2H), 8.87-8.92 (m, 1H) 321 (400 MHz, DMSO-D₆) 0.23-0.32(m, 2H), 0.32- 443 441 0.40 (m, 1.H), 0.54-0.62 (m, 1H), 0.87-0.94 (m,1H), 0.97 (s, 6H), 1.41-1.47 (m, 2H), 1.67 (s, 3H), 1.90- 1.94 (m, 2H),2.20-2.26 (m, 2H), 2.34-2.42 (m, 2H), 3.40-3.50 (m, 1H), 3.51-3.62 (m,1H), 5.52-5.55 (m, 1H), 5.92-5.96 (m, 1H), 7.11-7.15 (m, 1H), 7.15- 7.17(m, 1H), 7.17-7.20 (m, 1H), 7.27-7.33 (m, 1H), 7.35-7.39 (m, 1H) 322(400 MHz, DMSO-D₆) 0.64-0.69 (m, 3H), 0.93 (s, 493 491 9H), 1.00-1.05(m, 3H), 1.36-1.42 (m, 2H), 1.64 (s, 3H), 1.90-1.98 (m, 1H), 2.28 (s,6H), 2.62-2.71 (m, 2H), 5.99 (s, 1H), 7.12 (brs, 1H), 7.39-7.45 (m, 1H),7.52-7.61 (m, 2H), 12.41 (brs, 1H) 323 (400 MHz, DMSO-D₆) 0.95 (s, 9H),1.38-1.46 (m, 519 517 2H), 1.73 (s, 3H), 1.98-2.10 (m, 1H), 2.13-2.24(m, 1H), 2.66-2.73 (m, 2H), 3.09 (s, 3H), 3.16-3.25 (m, 2H), 6.42 (s,1H), 7.41-7.46 (m, 2H), 7.46-7.51 (m, 1H), 7.66-7.74 (m, 3H), 7.91-7.96(m, 2H) 324 (400 MHz, DMSO-D₆) 0.92 (s, 9H), 1.35-1.43 (m, 523 521 2H),1.60 (s, 3H), 1.74-1.79 (m, 2H), 1.79-1.83 (m, 4H), 1.87-1.91 (m, 2H),1.91-1.99 (m, 1H), 2.03- 2.13 (m, 1H), 2.62-2.70 (m, 2H), 3.06 (s, 3H),3.08- 3.21 (m, 2H), 5.97 (s, 1H), 7.10 (brs, 1H), 7.38-7.44 (m, 1H),7.53-7.59 (m, 1H), 7.60-7.65 (m, 1H), 12.27 (brs, 1H) 325 (400 MHz,DMSO-D₆) 0.94 (s, 9H), 1.30-1.44 (m, 525 523 4H), 1.49-1.57 (m, 2H),1.56-1.64 (m, 5H), 1.91- 2.05 (m, 3H), 2.07-2.24 (m, 2H), 2.63-2.71 (m,2H), 3.09 (s, 3H), 3.10-3.25 (m, 2H), 3.96-4.09 (m, 1H), 6.16 (s, 1H),7.18 (brs, 1H), 7.40-7.44 (m, 1H), 7.54- 7.59 (m, 1H), 7.61-7.64 (m,1H), 12.07 (brs, 1H) 326 (400 MHz, CDCl₃) 0.69-0.76 (m, 3H), 0.97 (s,9H), 529 527 1.04-1.10 (m, 3H), 1.42-1.50 (m, 2H), 1.76 (s, 3H),1.84-1.94 (m, 1H), 2.68-2.77 (m, 2H), 4.19-4.27 (m, 3H), 4.28-4.35 (m,3H), 5.18 (brs, 1H), 5.94 (s, 1H), 7.28-7.32 (m, 1H), 7.52-7.58 (m, 1H),7.62- 7.67 (m, 1H) 327 (400 MHz, DMSO-D₆) 0.72 (d, J = 6.94 Hz, 3H),1.04 453 451 (d, J = 6.94 Hz, 3H), 1.62 (s, 3H), 1.93-1.99 (m, 1H),2.10-2.20 (m, 2H), 2.45 (t, J = 6.82 Hz, 2H), 2.66- 2.75 (m, 2H),3.48-3.66 (m, 2H), 5.54-5.58 (m, 1H), 6.13 (s, 1H), 7.06 (s, 1H), 7.23(d, J = 8.09 Hz, 1H), 7.32 (dd, J = 8.09, 2.08 Hz, 1H), 7.39 (d, J =2.08 Hz, 1H), 12.25 (brs, 1H) 328 (400 MHz, DMSO-D₆) 0.69 (d, J = 6.94Hz, 3H), 1.03 455 453 (d J = 6.94 Hz, 3H), 1.61 (s, 3H), 1.63-1.70 (m,2H), 1.83-1.87 (m, 2H), 1.91-2.15 (m, 5H), 2.45 (t, J = 6.94 Hz, 2H),3.03-3.11 (m, 1H), 3.48-3.65 (m, 2H), 6.12 (s, 1H), 7.03 (s, 1H),7.30-7.38 (m, 3H), 12.25 (brs, 1H) 329 (400 MHz, DMSO-D₆) 0.80 (d, J =6.58 Hz, 6H), 1.40- 507 505 1.45 (m, 1H), 1.55 (s, 3H), 1.62-1.67 (m,2H), 1.85- 1.90 (m, 1H), 2.22-2.28 (m, 3H), 2.41-2.45 (m, 3H), 2.55-2.60(m, 4H), 2.69-2.75 (m, 1H), 2.88 (t, J = 9.87 Hz, 1H), 3.37-3.46 (m,1H), 4.91-5.01 (m, 1H), 6.41 (s, 1H), 7.25 (s, 1H), 7.27-7.35 (m, 3H),12.23 (s, 1H) 330 (400 MHz, DMSO-D₆) 0.80 (d, J = 6.70 Hz, 6H), 1.38-501 499 1.48 (m, 1H), 1.57 (s, 3H), 1.60-1.70 (m, 2H), 1.77- 1.99 (m,6H), 1.83 (s, 4H), 2.04-2.13 (m, 1H), 2.39- 2.47 (m, 2H), 3.12 (s, 3H),3.13-3.19 (m, 1H), 3.20- 3.27 (m, 1H), 3.37-3.47 (m, 1H), 5.94 (s, 1H),7.06 (s, 1H), 7.28-7.36 (m, 3H), 12.30 (brs, 1H) 331 (400 MHz, DMSO-D₆)0.98 (s, 6H), 1.46 (t, 461 459 J = 6.40 Hz, 2H), 1.58 (s, 3H), 1.86-1.95(m, 3H), 2.03- 2.11 (m, 1H), 2.21-2.27 (m, 2H), 2.44 (t, J = 6.94 Hz,2H), 3.12-3.28 (m, 5H), 3.47-3.62 (m, 2H), 5.54- 5.56 (m, 1H), 6.07 (s,1H), 7.14 (s, 1H), 7.19 (d, J = 7.98 Hz, 1H), 7.29 (dd, J = 7.98, 1.85Hz, 1H), 7.37 (d, J = 1.85 Hz, 1H), 12.24 (brs, 1H) 332 (400 MHz,DMSO-D₆) 0.98 (s, 6H), 1.46 (t, 509 507 J = 6.36 Hz, 2H), 1.70 (s, 3H),1.91-1.96 (m, 2H), 2.01- 2.10 (m, 1H), 2.15-2.28 (m, 3H), 3.12 (s, 3H),3.20- 3.29 (m, 2H), 5.55-5.58 (m, 1H), 6.40 (s, 1H), 7.25 (d, J = 7.91Hz, 1H), 7.40 (dd, J = 7.91, 1.97 Hz, 1H), 7.44-7.49 (m, 3H), 7.67 (s,1H), 7.91-7.96 (m, 2H), 12.90 (brs, 1H) 333 (400 MHz, DMSO-D₆) 0.98 (s,6H), 1.46 (t, 539 537 J = 6.36 Hz, 2H), 1.70 (s, 3H), 1.92-1.95 (m, 2H),2.00- 2.08 (m, 1H), 2.13-2.28 (m, 3H), 3.12 (s, 3H), 3.20- 3.30 (m, 2H),3.82 (s, 3H), 5.55-5.58 (m, 1H), 6.39 (s, 1H), 6.96 (dd, J = 8.32, 1.85Hz, 1H), 7.07 (d, J = 1.62 Hz, 1H), 7.25 (d, J = 7.86 Hz, 1H), 7.40 (dd,J = 7.98, 1.97 Hz, 1H), 7.48 (d, J = 1.85 Hz, 1H), 7.62 (s, 1H), 7.66(d, J = 8.55 Hz, 1H), 12.50 (s, 0H) 334 (400 MHz, DMSO-D₆) 0.98 (s, 6H),1.46 (t, 510 508 J = 6.36 Hz, 2H), 1.70 (s, 3H), 1.91-1.95 (m, 2H),2.05- 2.13 (m, 1H), 2.19-2.27 (m, 3H), 3.14 (s, 3H), 3.22- 3.26 (m, 2H),5.55-5.57 (m, 1H), 7.17 (s, 1H), 7.23 (d, J = 8.04 Hz, 1H), 7.37 (dd, J= 8.04, 1.91 Hz, 1H), 7.45 (d, J = 1.91 Hz, 1H), 7.81-7.86 (m, 2H), 8.14(dd, J = 8.67, 2.03 Hz, 1H), 8.81 (d, J = 2.03 Hz, 1H) 335 (400 MHz,DMSO-D₆) 0.92-1.03 (m, 2H), 1.09- 449 447 1.18 (m, 3H), 1.50-1.68 (m,9H), 1.85-1.93 (m, 1H), 2.00-2.09 (m, 1H), 2.44 (t, J = 6.94 Hz, 2H),2.56 (d, J = 6.94 Hz, 2H), 3.05-3.12 (m, 4H), 3.15-3.22 (m, 1H),3.47-3.63 (m, 2H), 6.06 (s, 1H), 7.11 (s, 1H), 7.22-7.28 (m, 2H), 7.36(d, J = 1.39 Hz, 1H), 12.25 (brs, 1H) 336 (400 MHz, DMSO-D₆) 0.95-1.05(m, 2H), 1.10- 497 495 1.17 (m, 3H), 1.53-1.70 (m, 9H), 1.99-2.07 (m,1H), 2.13-2.21 (m, 1H), 2.58 (d, J = 6.70 Hz, 2H), 3.10 (s, 3H),3.13-3.28 (m, 2H), 6.39 (s, 1H), 7.28-7.31 (m, 1H), 7.35-7.37 (m, 1H),7.45-7.49 (m, 3H), 7.64 (s, 1H), 7.92-7.96 (m, 2H), 12.89 (s, 1H) 337(400 MHz, DMSO-D₆) 0.96-1.03 (m, 2H), 1.10- 527 525 1.18 (m, 3H),1.53-1.71 (m, 9H), 1.98-2.06 (m, 1H), 2.12-2.20 (m, 1H), 2.58 (d, J =6.70 Hz, 2H), 3.10 (s, 3H), 3.12-3.28 (m, 2H), 3.82 (s, 3H), 6.38 (s,1H), 6.93-6.97 (m, 1H), 7.05-7.07 (m, 1H), 7.30 (d, J = 8.15 Hz, 1H),7.37 (dd, J = 8.15, 2.14 Hz, 1H), 7.46 (d, J = 2.14 Hz, 1H), 7.59 (s,1H), 7.63-7.67 (m, 1H) 338 (400 MHz, DMSO-D₆) 0.93-1.04 (m, 2H), 1.09-498 496 1.18 (m, 3H), 1.52-1.72 (m, 9H), 2.02-2.11 (m, 1H), 2.17-2.26(m, 1H), 2.57 (d, J = 6.00 Hz, 2H), 3.11 (s, 3H), 3.21 (d, J = 14.57 Hz,2H), 7.24-7.34 (m, 3H), 7.42 (d, J = 1.85 Hz, 1H), 7.95 (s, 1H), 8.04(dd, J = 8.79, 0.69 Hz, 1H), 8.22 (dd, J = 8.79, 2.54 Hz, 1H), 8.87-8.89 (m, 1H) 339 (400 MHz, DMSO-D₆) 0.88-1.03 (m, 2H), 0.91 (s, 447 4459H), 1.09-1.18 (m, 3H), 1.52-1.69 (m, 6H), 1.77 (s, 3H), 2.41-2.47 (m,2H), 2.55 (d, J = 6.45 Hz, 2H), 3.47- 3.54 (m, 1H), 3.71-3.64 (m, 1H),6.29 (s, 1H), 6.85 (s, 1H), 7.20 (d, J = 8.06 Hz, 1H), 7.25 (dd, J =8.46, 2.01 Hz, 1H), 7.35 (d, J = 2.01 Hz, 1H) 340 (400 MHz, DMSO-D₆)0.94 (s, 9H), 1.37-1.44 (m, 509 507 2H), 1.61 (s, 3H), 1.87-1.98 (m,1H), 2.02-2.13 (m, 1H), 2.25 (s, 6H), 2.64-2.72 (m, 2H), 3.05-3.14 (m,4H), 3.14-3.22 (m, 1H), 6.03 (s, 1H), 7.20-7.24 (m, 1H), 7.42-7.47 (m,1H), 7.54-7.59 (m, 1H), 7.59- 7.64 (m, 1H), 12.49 (brs, 1H) 341 (400MHz, CDCl₃) 0.96 (s, 9H), 1.41-1.48 (m, 2H), 541 539 1.70 (s, 3H),1.87-2.13 (m, 2H), 2.28-2.44 (m, 2H), 2.50 (s, 6H), 2.57-2.68 (m, 1H),2.68-2.76 (m, 2H), 5.18 (brs, 1H), 5.86 (s, 1H), 7.27-7.32 (m, 1H),7.44- 7.50 (m, 1H), 7.57-7.61 (m, 1H) 342 (400 MHz, CDCl₃) 0.98 (s, 9H),1.44-1.51 (m, 2H), 551 549 1.84 (s, 3H), 1.96-2.24 (m, 2H), 2.37-2.57(m, 2H), 2.63-2.81 (m, 3H), 5.44 (brs, 1H), 6.24 (s, 1H), 7.32- 7.40 (m,1H), 7.45-7.54 (m, 2H), 7.55-7.63 (m, 1H), 7.67-7.72 (m, 1H), 8.08-8.18(m, 2H) 343 (400 MHz, CDCl₃) 0.96-1.00 (m, 9H), 1.42-1.50 503 501 (m,2H), 1.71 (s, 3H), 1.88-2.13 (m, 2H), 2.29-2.45 (m, 2H), 2.59-2.67 (m,2H), 2.68-2.77 (m, 2H), 3.69- 3.75 (m, 1H), 3.75-3.88 (m, 2H), 5.81(brs, 1H), 5.95 (s, 1H), 7.28-7.33 (m, 1H), 7.48-7.54 (m, 1H), 7.60-7.63(m, 1H) 344 (400 MHz, CDCl₃) 0.82 (s, 9H), 1.65-1.69 (m, 3H), 515 5131.71-1.85 (m, 3H), 1.85-1.97 (m, 2H), 1.98-2.03 (m, 3H), 2.03-2.18 (m,6H), 2.24-2.37 (m, 2H), 3.14- 3.26 (m, 5H), 3.35-3.47 (m, 1H), 4.88(brs, 1H), 5.84 (s, 1H), 7.18-7.28 (m, 2H), 7.32-7.37 (m, 1H) 345 (400MHz, CDCl₃) 0.73-0.78 (m, 3H), 0.96 (s, 9H), 533 531 1.09-1.14 (m, 3H),1.43-1.49 (m, 2H), 1.85 (s, 3H), 1.90-2.00 (m, 1H), 2.69-2.78 (m, 2H),4.10 (s, 3H), 4.92 (s, 1H), 6.24 (s, 1H), 6.99-7.04 (m, 1H), 7.30- 7.37(m, 2H), 7.56-7.62 (m, 1H), 7.69-7.72 (m, 1H), 8.18-8.25 (m, 1H),10.44-10.67 (m, 1H) 346 (400 MHz, CDCl₃) 0.97 (s, 9H), 1.41-1.49 (m,2H), 547 545 1.78 (s, 3H), 1.97-2.26 (m, 2H), 2.33-2.59 (m, 2H),2.62-2.76 (m, 3H), 4.10 (s, 3H), 4.98 (brs, 1H), 6.19- 6.23 (m, 1H),7.00-7.07 (m, 1H), 7.20-7.29 (m, 2H), 7.30-7.34 (m, 1H), 7.42-7.45 (m,1H), 8.20-8.26 (m, 1H), 10.51 (brs, 1H) 347 (400 MHz, CDCl₃) 0.16-0.24(m, 1H), 0.25-0.32 431 429 (m, 1H), 0.33-0.43 (m, 1H), 0.56-0.65 (m,1H), 0.82- 0.91 (m, 1H), 0.91-1.06 (m, 2H), 1.09-1.30 (m, 4H), 1.55-1.76(m, 6H), 1.79 (s, 3H), 2.54-2.65 (m, 4H), 3.65-3.81 (m, 2H), 5.66 (brs.1H), 5.70-5.72 (m, 1H), 7.11-7.15 (m, 1H), 7.25-7.29 (m, 1H), 7.40- 7.44(m, 1H) 348 (400 MHz, DMSO-D₆) 0.94 (d, J = 6.47 Hz, 6H), 1.63 519 517(t, J = 6.82 Hz, 2H), 1.67 (s, 3H), 1.76-1.86 (m, 1H), 2.21-2.40 (m,2H), 2.56-2.67 (m, 3H), 4.09 (t, J = 6.59 Hz, 2H), 6.49 (d, J = 0.92 Hz,1H), 7.16 (d, J = 8.79 Hz, 1H), 7.36 (dd, J = 8.67, 2.43 Hz, 1H), 7.47(d, J = 2.54 Hz, 1H), 7.50-7.53 (m, 2H), 7.67 (s, 1H), 7.94-7.96 (m,2H), 12.90 (brs, 1H) 349 (400 MHz, DMSO-D₆) 0.93 (d, J = 6.47 Hz, 6H),1.55 509 507 (s, 3H), 1.65-1.60 (m, 2H), 1.75-1.86 (m, 1H), 2.18- 2.28(m, 2H), 2.32 (s, 6H), 2.42-2.55 (m, 2H), 2.66- 2.75 (m, 1H), 4.07 (t, J= 6.59 Hz, 2H), 6.03 (d, J = 1.16 Hz, 1H), 7.13 (d, J = 8.70 Hz, 1.H),7.21 (s, 1H), 7.24 (dd, J = 8.70, 2.43 Hz, 1H), 7.35 (d, J = 2.43 Hz,1H), 12.46 (brs, 1H) 350 (400 MHz, DMSO-D₆) 0.12-0.16 (m, 2H), 0.41- 517515 0.46 (m, 2H), 0.81-0.89 (m, 1H), 1.64 (t, J = 6.47 Hz, 2H), 1.68 (s,3H), 2.21-2.37 (m, 2H), 2.54-2.74 (m, 3H), 4.12 (t, J = 6.47 Hz, 2H),6.49 (d, J = 0.92 Hz, 1H), 7.16 (d, J = 8.70 Hz, 1H), 7.37 (dd, J =8.70, 2.50 Hz, 1H), 7.47 (d, J = 2.50 Hz, 1H), 7.50-7.53 (m, 2H), 7.67(s, 1H), 7.93-7.97 (m, 2H), 12.90 (brs, 1H) 351 (400 MHz, DMSO-D₆) 0.70(d, J = 6.94 Hz, 3H), 0.95 503 501 (s, 9H), 1.35-1.41 (m, 2H), 1.56-1.77(m, 11H), 1.99-2.06 (m, 1H), 2.61-2.65 (m, 2H), 3.11 (t, J = 8.90 Hz,1H), 3.22 (s, 4H), 5.93 (s, 1H), 6.91 (s, 1H), 7.25-7.35 (m, 3H) 352(400 MHz, DMSO-D₆) 0.95 (s, 10H), 1.03 (d, 503 501 J = 6.70 Hz, 3H),1.35-1.40 (m, 2H), 1.61-1.79 (m, 11H), 2.00-2.06 (m, 1H), 2.61-2.67 (m,3H), 2.86- 2.91 (m, 1H), 2.93 (s, 3H), 5.90 (s, 1H), 6.95 (s, 1H),7.25-7.32 (m, 2H), 7.37 (d, J = 1.85 Hz, 1H) 353 (400 MHz, DMSO-D₆) 1.03(s, 9H), 1.67 (s, 3H), 2.38- 519 517 2.21 (m, 2H), 2.54-2.79 (m, 3H),3.72 (s, 2H), 6.49 (d, J = 0.92 Hz, 1H), 7.12 (d, J = 8.79 Hz, 1H), 7.36(dd J = 8.55, 2.31 Hz, 1H), 7.47 (d, J = 2.31 Hz, 1H), 7.50- 7.53 (m,2H), 7.67 (s, 1H), 7.93-7.97 (m, 2H), 12.90 (brs, 1H) 354 (400 MHz,DMSO-D₆) 0.16-0.12 (m, 2H), 0.45- 507 505 0,41 (m, 2H), 0.81-0.88 (m,1H), 1.56 (s, 3H), 1.61- 1.67 (m, 2H), 2.19-2.28 (m, 2H), 2.32 (s, 6H),2.44- 2.57 (m, 2H), 2.66-2,74 (m, 1H), 4.10 (t, J = 6.47 Hz, 2H), 6.03(d, J = 1.16 Hz, 1H), 7.12 (d, J = 8.79 Hz, 1H), 7.21 (s, 1H), 7.24 (dd,J = 8.67, 2.43 Hz, 1H), 7.35 (d J = 2.54 Hz, 1H), 12.44 (brs, 1H) 355(400 MHz, DMSO-D₆) 1.02 (s, 9H), 1.55 (s, 3H), 2.28- 509 507 2.19 (m,2H), 2.32 (s, 6H), 2.44-2.52 (m, 2H), 2.66- 2.74 (m, 1H), 3.70 (s, 2H),6.04 (d, J = 1.16 Hz, 1H), 7.08 (d, J = 8.55 Hz, 1H), 7.21 (s, 1H), 7.23(dd, J = 8.55, 2.31 Hz, 1H), 7.35 (d, J = 2.31 Hz, 1H), 12.44 (brs, 1H)356 (400 MHz, DMSO-D₆) 0.70-0.76 (m, 3H), 0.94 (s, 453 451 9H),1.06-1.11 (m, 3H), 1.37-1.46 (m, 2H), 1.71 (s, 3H), 2.02-2.10 (m, 1H),2.52-2.61 (m, 2H), 6.26 (s, 1H), 7.14-7.21 (m, 3H), 7.21-7.27 (m, 1H),7.27- 7.34 (m, 1H), 7.34-7.37 (m, 1H), 7.80-7.87 (m, 2H) 357 (400 MHz,DMSO-D₆) 1.55 (s, 3H), 1.73-1.64 (m, 521 519 2H), 1.76-1.87 (m, 4H),2.01-2.08 (m, 2H), 2.17- 2.28 (m, 2H), 2.32 (s, 6H), 2.41-2.51 (m, 3H),2.66- 2.74 (m, 1H), 3.98 (t, J = 6.47 Hz, 2H), 6.03 (d, J = 1.16 Hz,1H), 7.09 (d, J = 8.79 Hz, 1H), 7.21 (s, 1H), 7.23 (dd, J = 8.67, 2.43Hz, 1H), 7.34 (d, J = 2.31 Hz, 1H), 12.45 (brs, 1H)

Formulation examples of the present invention include for example thefollowing, but the present invention should not be construed as beinglimited thereto.

Formulation Example 1 (Preparation of a Capsule)

1) Compound of Example 1 30 mg 2) Microcrystalline cellulose 10 mg 3)Lactose 19 mg 4) Magnesium stearate  1 mg

-   -   1), 2), 3), and 4) are mixed and filled in a gelatin capsule.

Formulation Example 2 (Preparation of a Tablet)

1) Compound of Example 1 10 g 2) Lactose 50 g 3) Corn starch 15 g 4)Carmellose calcium 44 g 5) Magnesium stearate  1 g

The entire amounts of 1), 2) and 3) and 30 g of 4) are mixed with waterand dried in vacuo and then granulated. The granulated powder is mixedwith 14 g of 4) and 1 g of 5) and tableted by a tableting machine. Inthis way, 1000 tablets can be obtained, each of which contains 10 mg ofCompound of Example 1.

Test Example 1

Pharmacological effects of the typical compounds of the presentinvention were observed.

In Vitro Assay of Inhibitory Effect Against RORγ TranscriptionalActivity

Inhibitory effect of a test article on transcriptional activity of RORγwas measured by means of the following reporter gene assay.

cDNA encoding human and mouse RORγ ligand binding domain (LBD) wereobtained based on the sequences of human RORγ (Genebank registerednumber NM_005060.3) and mouse RORγ (Genebank registered numberNM_011281.2) (LBD sequence: human RORγ, from Ser253 to Lys518; mouseRORγ, from Ile251 to Lys516).

The LBD cDNA of human or mouse RORγ was inserted into pFA-CMV vector(Strategene), which expresses GAL4-DNA binding domain fusion protein.The resulting plasmids are hereinafter referred to as GAL4-hRORγ plasmidand GAL4-mRORγ plasmid, respectively.

GAL4-hRORγ plasmid or GAL4-mRORγ plasmid was transiently co-transfectedinto Chinese hamster ovary cells (CHO cells) with pG5-Luc (Promega), areporter plasmid expressing firefly luciferase depending on GAL4.

TransIT (Registered trademark) CHO transfection reagent (Mims) was usedto cotransfect GAL4-hRORγ plasmid or GAL4-mRORγ plasmid into CHO cellswith pG5-Luc plasmid. One day before the assay, CHO cells were suspendedin HAM F-12 Nutrient medium containing 10 v/v % fetal bovine serum andseeded at 6×10⁶ cells per 175 cm² cell culture flask. Fifty four microlitters of TransIT (Registered trademark) CHO reagent was added into a15 ml tube containing 1.16 mL of HAM F-12 Nutrient medium without fetalbovine serum, and mixed and incubated at room temperature for 10 min.Thirty six micro litters of plasmid solution containing the GAL4-hRORγplasmid (400 ng), pG5-Luc plasmid (9000 ng) and pcDNA3 plasmid (8600 ng)were added into the tube and mixed gently. In case of mouse assay, aplasmid solution containing the GAL4-mRORγ plasmid (250 ng). pG5-Lucplasmid (9000 ng) and pcDNA3 plasmid (8750 ng) was added, instead. Themixture was incubated at room temperature for 10 min. Nine micro littersof CHO Mojo Reagent were then added into each tube and mixed gently. Themixture was incubated at room temperature for 10 min. The resultanttransfection reagent was applied to the cell culture. After incubationat 37° C., 5% CO₂ for 4 hours, the plasmid-transfected CHO cells wereharvested with a trypsin treatment. The collected cells were resuspendedin HAM F-12 Nutrient medium supplemented with 10 v/v % fetal bovineserum and plated into a 384-well-white plate at 8,000 cells/50 μL/well.The plate was incubated at room temperature for 1 hour and then furtherincubated at 37° C., 5% CO₂ for 3 hours. The test articles weredissolved in dimethylsulfoxide (DMSO) to obtain a concentration of 10mM. The resulting solution was diluted with a medium just before use andadded to the cells in the plate to prepare 8 different concentrations ofthe test article. The final concentration of DMSO was 0.2 v/v %. Afterthe addition of the test articles, the cells were incubated at 37° C.,5% CO₂ for 2 days.

Cell viability was tested by a fluorescence method using Resazurin(invitrogen). Two days after the addition of the test article, Resazurinwas diluted with a medium to make the 20 resazurin solution. Ten microlitters of the diluted Resazurin solution was added into the384-well-plate. Then, the fluorescence was measured immediately at 615nm with the excitation wavelength of 570 nm (0 hr reading). Afterincubation at 37° C., 5% CO₂ for 2 hours, the fluorescence was measuredat 615 nm with the excitation wavelength of 570 nm again (2 hourreading). The fluorescence counts (2 hr-0 hr) were calculated bysubtracting the 0 hr readings from the 2 hr readings. The luminescencecount (2 h-0 h) in the cells treated with 0.2% DMSO alone was defined as100%, and the cell viability in the test article was calculated as apercentage (%—of—control) based on the value of 0.2% DMSO alone. Whenthe cell viability is 70% or less, it was judged that the test articlehas cytotoxicity.

RORγ transcriptional activity was detected as the intracellularluciferase activity using SteadyLite HTS Reporter Gene Assay System(Perkin Elmer). SteadyLite Reagent was diluted five-fold into a solutioncontaining Extension reagent (10 mM Tricine, 0.2% w/v BSA, 0.02% v/vTween-20) to obtain the luciferase substrate solution. After themeasurement of the cell viability using Resazurin, the culture media inthe plate were removed, and then the luciferase substrate solution wasadded into each well. After the incubation at room temperature for 10minutes, luminescence of each well was measured by a microplate reader.The luciferase activity derived from the luminescence count in thevehicle-control well treated with 0.2% DMSO alone was defined as 100%,and the luciferase activity in the test article was calculated as apercentage (%—of—control) based on the value of the vehicle-control.EC₅₀ value of test article was calculated by curve fitting with GraphPadPrism. The luminescence counts at the concentration of the test articlewhere the cytotoxicity was observed were excluded from the dataanalysis.

The results are shown in the table below.

The values with % is the activity of the test article which wascalculated as a percentage (%—of—control) based on the value of thevehicle-control treated with 0.2% DMSO alone (100%).

In the following table, compounds of Examples 38, 87, and 116 weresynthesized by a preparation method using Claisen reaction and measured.

TABLE 5 LUC EC₅₀(μM) Example hRORγ mRORγ 1 0.088 0.060 2 >20 (55%)13.060 3 0.182 0.061 4 1.443 0.675 5 0.034 0.024 6 >8 (76%) >8 (75%) 70.152 0.110 8 0.021 0.022 9 0.055 0.032 10 0.009 0.017 11 >8 (87%) >8(79%) 12 0.023 0.017 13 6.572 5.926 14 >8 (69%) >8 (59%) 15 0.012 0.01216 0.362 0.137 17 0.206 0.153 18 0.051 0.028 19 2.285 1.209 20 2.9352.519 21 0.019 0.024 22 0.017 0.029 23 0.042 0.041 24 2.938 2.934 25<0.032 <0.032 26 0.364 0.217 27 0.025 0.016 28 0.187 0.082 29 0.0360.049 30 0.060 0.047 31 3.074 >3.2 (52%) 32 0.026 0.046 33 0.435 0.61734 0.013 0.021 35 >3.2 (51%) >3.2 (52%) 36 0.021 0.024 37 0.154 0.282 380.011 0.015 39 0.020 0.026 40 0.152 0.198 41 >8 (59%) >8 (61%) 42 0.0310.028 43 0.564 0.835 44 0.051 0.090 45 7.330 7.508 46 0.017 0.016 471.103 0.764 48 0.012 0.016 49 0.983 0.832 50 0.007 0.013 51 1.181 1.08352 0.010 0.015 53 0.036 0.021 54 >8 (92%) >8 (81%) 55 0.022 0.026 565.163 4.291 57 0.031 0.022 58 1.249 1.654 59 0.012 0.020 60 15.27012.430 61 0.143 0.046 62 0.665 0.520 63 >8 (51%) >8 (70%) 64 0.019 0.01665 0.028 0.021 66 3.609 2.681 67 0.023 0.017 68 1.236 1.756 69 0.0200.017 70 0.251 0.133 71 0.505 0.758 72 0.013 0.017 73 0.803 0.657 740.986 1.103 75 0.296 0.316 76 3.472 6.358 77 0.015 0.024 78 6.490 10.76079 0.016 0.018 80 0.016 0.017 81 2.579 2.487 82 0.980 0.790 83 0.0400.043 84 0.746 0.502 85 0.545 0.368 86 6.770 >8 (51%) 87 0.011 0.015 880.443 0.422 89 0.016 0.016 90 0.015 0.018 91 0.539 1.152 92 0.013 0.02093 2.144 2.544 94 0.152 0.142 95 >3.2 (66%) 5.685 96 0.033 0.026 971.344 3.097 98 0.013 0.018 99 1.507 2.886 100 0.020 0.035 101 0.0320.021 102 >8 (76%) >8 (76%) 103 >3.2 (65%) >3.2 (50%) 104 0.050 0.031105 2.792 1.691 106 1.162 0.616 107 3.930 1.976 108 0.016 0.021 109 >8(60%) >8 (67%) 110 0.011 0.010 111 0.405 0.481 112 0.021 0.019 113 3.0311.399 114 14.880 10.960 115 >8 (110%) >8 (100%) 116 0.015 0.022 117 >3.2(106%) >8 (76%) 118 0.019 0.017 119 >8 (74%) >8 (76%) 120 0.061 0.014121 >8 (62%) >8 (85%) 122 0.028 0.015 123 >3.2 (109%) >3.2 (100%)124 >0.512 (54%) 0.030 125 <0.032 <0.032 126 0.037 0.027 127 2.940 1.950128 >20 (66%) >20 (54%) 129 0.047 <0.032 130 0.010 0.019 131 >8 (77%) >8(81%) 132 0.018 0.014 133 >8 (71%) >8 (88%) 134 0.070 0.027 135 >8(90%) >8 (84%) 136 0.094 0.049 137 0.015 0.011 138 >8 (85%) >8 (96%)139 >0.512 (110%) 0.027 140 0.209 0.139 141 >8 (57%) >8 (52%) 142 >0.512(102%) 0.049 143 >8 (90%) >8 (100%) 144 >0.512 (60%) 0.037 145 2.0383.973 146 0.014 0.012 147 0.059 0.030 148 >8 (57%) >8 (69%) 149 1.0140.245 150 0.021 0.012 151 0.018 0.023 152 >20 (56%) >20 (57%) 153 0.3270.116 154 0.010 0.014 155 >8 (83%) >8 (81%) 156 0.520 0.166 157 0.4970.255 158 0.030 0.023 159 0.021 0.023 160 0.015 0.040 161 0.154 0.047162 0.172 0.275 163 0.143 0.267 164 0.018 0.011 165 0.027 0.017 1660.014 0.029 167 0.065 0.049 168 0.012 0.018 169 0.008 0.015 170 0.0580.040 171 0.012 0.014 172 0.013 0.018 173 0.022 0.011 174 0.014 0.011175 0.009 0.012 176 0.022 0.013 177 0.017 0.017 178 0.019 0.021 1790.064 0.027 180 0.032 0.050 181 0.018 0.032 182 0.027 0.076 183 0.1180.078 184 0.011 0.022 185 0.009 0.014 186 0.091 0.116 187 0.172 0.063188 2.606 1.129 189 0.030 0.022

TABLE 6 LUC EC₅₀(μM) Example hRORγ mRORγ 190 >8 (74%) >8 (66%) 191 0.0450.071 192 0.017 0.011 193 0.018 0.019 194 0.058 0.028 195 0.018 0.012196 0.009 0.017 197 0.013 0.023 198 0.012 0.026 199 0.070 0.136 2000.014 0.023 201 0.060 0.051 202 0.087 0.052 203 0.030 0.021 204 0.0140.017 205 0.281 0.427 206 0.081 0.117 207 0.009 0.018 208 0.021 0.040209 0.051 0.074 210 0.006 0.007 211 0.011 0.008 212 >8 (68%) >8 (81%)213 0.131 0.056 214 0.169 0.100 215 >20 (77%) >20 (70%) 216 >20(86%) >20 (76%) 217 >20 (90%) >20 (77%) 218 0.376 0.122 219 >20(88%) >20 (86%) 220 0.022 0.029 221 0.025 0.024 222 0.020 0.040 223 >20(78%) >20 (70%) 224 0.343 0.123 225 0.101 0.072 226 0.017 0.020 227 >20(89%) >20 (87%) 228 0.032 0.032 229 0.009 0.018 230 0.225 0.076 2310.692 0.458 232 0.015 0.019 233 0.069 0.072 234 0.964 0.534 235 >3.2(70%) 1.610 236 0.020 0.015 237 0.719 0.673 238 0.715 0.666 239 4.5623.065 240 0.108 0.147 241 0.112 0.247 242 0.078 0.058 243 1.219 0.543244 0.176 0.269 245 0.261 0.301 246 0.010 0.022 247 0.018 0.016 2480.010 0.021 249 0.412 0.779 250 0.042 0.114 251 0.013 0.028 252 0.0200.028 253 0.075 0.034 254 0.028 0.028 255 0.273 0.296 256 0.022 0.026257 0.165 0.115 258 0.022 0.016 259 0.057 0.043 260 0.439 0.492 261 >20(90%) >20 (100%) 262 0.022 0.022 263 0.026 0.018 264 0.045 0.033 2650.037 0.071 266 0.012 0.017 267 0.030 0.033 268 0.015 0.014 269 0.0190.023 270 0.052 0.026 271 0.043 0.047 272 0.017 0.036 273 0.025 0.075274 0.008 0.008 275 0.542 1.215 276 0.028 0.047 277 0.023 0.038 2780.013 0.013 279 0.016 0.022 280 0.026 0.042 281 0.014 0.021 282 0.3780.187 283 0.018 0.028 284 2.785 1.503 285 1.353 0.030 286 0.270 0.038287 0.036 0.034 288 1.491 0.917 289 1.117 0.773 290 0.463 0.259 2911.085 0.138 292 0.089 0.073 293 1.095 1.019 294 0.068 0.034 295 0.1340.366 296 3.721 4.533 297 0.044 0.061 298 0.022 0.018 299 0.011 0.016300 0.010 0.014 301 0.027 0.010 302 0.028 0.030 303 1.399 1.308 3040.021 0.019 305 0.003 0.006 306 0.063 0.027 307 0.005 0.013 308 0.0320.025 309 >3.2 (63%) 0.071 310 0.476 0.277 311 0.086 0.094 312 0.2480.538 313 0.260 0.366 314 0.038 0.032 315 0.013 0.019 316 0.018 0.019317 0.040 0.024 318 0.017 0.014 319 0.013 0.014 320 0.023 0.027 3210.060 0.048 322 0.021 0.019 323 0.051 0.023 324 0.047 0.036 325 0.1740.060 326 0.032 0.036 327 0.058 0.040 328 0.035 0.019 329 0.074 0.050330 0.019 0.014 331 0.014 0.008 332 0.012 0.013 333 0.023 0.013 3340.022 0.014 335 0.026 0.011 336 0.010 0.007 337 0.022 0.014 338 0.0130.012 339 0.017 0.015 340 0.123 0.043 341 0.067 0.032 342 0.043 0.028343 0.038 0.019 344 0.013 0.012 345 0.042 0.023 346 0.026 0.018 3470.109 0.035 348 0.046 0.039 349 0.063 0.045 350 0.109 0.052 351 0.0040.011 352 0.063 0.051 353 0.059 0.045 354 0.239 0.144 355 0.113 0.052356 0.021 0.015 357 0.034 0.029

INDUSTRIAL APPLICABILITY

The compound of Formula [I] or a pharmaceutically acceptable saltthereof is useful in treating or preventing autoimmune disease such asrheumatoid arthritis, psoriasis, inflammatory bowel disease such asCrohn's disease and ulcerative colitis, multiple sclerosis, systemiclupus erythematosus, ankylosing spondylitis, uveitis, polymyalgiarheumatic, type I diabetes, and graft versus host disease; allergicdisease such as asthma; dry eye; fibrosis such as pulmonary fibrosis andprimary biliary cirrhosis; and metabolic disease such as diabetes.

1-37. (canceled)
 38. A method of inhibiting RORγ, comprisingadministering to a mammal a therapeutically effective amount of acompound selected from the group consisting of:

or a pharmaceutically acceptable salt of any of the foregoing.
 39. Themethod of claim 38, wherein the compound is:

or a pharmaceutically acceptable salt thereof.
 40. The method of claim38, wherein the compound is:

or a pharmaceutically acceptable salt thereof.
 41. The method of claim38, wherein the compound is:

or a pharmaceutically acceptable salt thereof.
 42. The method of claim38, wherein the compound is:

or a pharmaceutically acceptable salt thereof.
 43. The method of claim38, wherein the compound is:

or a pharmaceutically acceptable salt thereof.
 44. The method of claim38, wherein the compound is:

or a pharmaceutically acceptable salt thereof.
 45. The method of claim38, wherein the compound is:

or a pharmaceutically acceptable salt thereof.
 46. A method of treatinga disease selected from the group consisting of allergic disease, dryeye, fibrosis, and metabolic disease, comprising administering to amammal an effective amount of a compound selected from the groupconsisting of:

or a pharmaceutically acceptable salt of any of the foregoing.
 47. Themethod of claim 46, wherein the compound is:

or a pharmaceutically acceptable salt thereof.
 48. The method of claim46, wherein the compound is:

or a pharmaceutically acceptable salt thereof.
 49. The method of claim46, wherein the compound is:

or a pharmaceutically acceptable salt thereof.
 50. The method of claim46, wherein the compound is:

or a pharmaceutically acceptable salt thereof.
 51. The method of claim46, wherein the compound is:

or a pharmaceutically acceptable salt thereof.
 52. The method of claim46, wherein the compound is:

or a pharmaceutically acceptable salt thereof.
 53. The method of claim46, wherein the compound is:

or a pharmaceutically acceptable salt thereof.
 54. The method accordingto any one of claims 46 to 53, wherein the disease is allergic disease.55. The method according to any one of claims 46 to 53, wherein thedisease is dry eye.
 56. The method according to any one of claims 46 to53, wherein the disease is fibrosis.
 57. The method according to any oneof claims 46 to 53, wherein the disease is metabolic disease.
 58. Amethod of preparing a compound of Formula [Q-109]:

the method comprising reacting a compound of Formula [Q-107]:

with a compound of Formula [Q-108]:H₂N—R^(5q)  [Q108] in a solvent and optionally in the presence of abase, wherein R¹ is (1) C₄₋₈ alkyl, (2) C₃₋₈ alkyl substituted with onehydroxy, (3) C₄₋₈ alkyl substituted with one halogen, (4) C₄₋₈ alkenyl,(5) C₄₋₈ alkynyl, (6) C₃₋₇ alkyl substituted with one trifluoromethyl,(7) C₁₋₅ alkyl substituted with one substituent selected from GroupX^(a1), (8) C₃₋₆ alkoxy, (9) C₂₋₇ alkoxy substituted with onetrifluoromethyl, (10) C₁₋₃ alkoxy substituted with one substituentselected from Group X^(a2), (11) C₄₋₆ cycloalkyl, (12) C₃₋₆ cycloalkylsubstituted with the same or different one to two C₁₋₅ alkyl, (13) C₅₋₆cycloalkenyl optionally substituted with the same or different one totwo C₁₋₄ alkyl, (14) spiro C₆₋₁₁ cycloalkyl, (15) C₁₋₃ alkoxycarbonyl,(16) C₃₋₆ alkylsulfanyl, (17) C₃₋₆ alkylsulfinyl, (18) C₃₋₆alkylsulfonyl, (19) C₃₋₆ cycloalkylsulfanyl, (20) C₃₋₆cycloalkylsulfinyl, (21) C₃₋₆ cycloalkylsulfonyl, (22)cyclobutylidenemethyl, (23) cyclopentylidenemethyl, (24)cyclohexylidenemethyl optionally substituted with the same or differentone to two C₁₋₃ alkyl, (25) tetrahydropyran-4-ylidenemethyl, (26) C₃₋₆cycloalkyl substituted with one to the same two halogen, or (27) C₅₋₆cycloalkenyl substituted with one to the same two halogen; Group X^(a1)is (a) C₃₋₆ cycloalkyl optionally substituted with the same or differentone to three C₁₋₅ alkyl, (b) C₃₋₆ cycloalkyl substituted with the sameor different one to two halogen, (c) phenyl, (d) C₂₋₄ alkoxy, (e)trimethylsilyl, (f) carboxy, or (g) tetrahydropyran-4-yl; Group X^(a2)is (a) C₃₋₆ cycloalkyl, (b) phenyl, or (c) C₁₋₄ alkoxy; R² is (1)halogen, (2) C₁₋₆ alkyl, (3) C₁₋₃ alkoxy optionally substituted withphenyl, or (4) trifluoromethyl; n is an integer of 0, 1 or 2, providedthat when n is 2, each R² may be different from each other; or R¹ and R²may combine together with the benzene ring to which they attach to formindanyl where the indanyl may be substituted with the same or differentone to two C₁₋₆ alkyl; R^(3q)i is —Y^(b)—CH₂OP², C₁₋₆ alkyl optionallysubstituted with hydroxy protected with one P², C₃₋₆ cycloalkyloptionally substituted with the same or different one to threesubstituents from Group X^(b), 4-tetrahydropyranyl, orI-methanesulfonyl-3-azetidinyl; Y^(b) is C₁₋₆ alkylene or C₃₋₆cycloalkylene; P² is a protective group selected from the groupconsisting of trimethylsilyl (TMS) and tertbutyldimethylsilyl; GroupX^(b) is halogen or C₁₋₆ alkyl; R⁴ is (1) hydrogen or (2) methyl; R^(5q)is —Y^(c)—COO—R⁵⁰, hydrogen, C₁₋₄ alkyl optionally substituted with oneC₁₋₃ alkoxy, or C₃₋₆ cycloalkyl optionally substituted with hydroxy-C₁₋₄alkyl protected with one P²; R^(q50) is C₁₋₄ alkyl; Y^(c) is C₁₋₆alkylene optionally substituted with hydroxy protected with one P²,CH₂—CH₂—O—CH₂, or (CH₂)_(m)—Y^(c1)—(CH₂)_(w); m is an integer of 0, 1,or 2; w is an integer of 0, 1, or 2; and Y^(c1) is C₃₋₆ cycloalkyleneoptionally substituted with one C₁₋₃ alkyl, phenylene, crosslinked C₅₋₈cycloalkylene, or

 and R⁶ is (1) hydrogen or (2) methyl.
 59. The method of claim 58,wherein the base is triethylamine; and the solvent is benzene, toluene,dichloromethane, chloroform, diethyl ether, tetrahydrofuran,1,2-dimethoxyethane, ethyl acetate, N,N-dimethylformamide,dimethylsulfoxide, acetonitrile, acetone, or any mixture of theforegoing; and the reacting is carried out at a temperature of from 0°C. to 80° C.
 60. The method of claim 58, wherein the compound of Formula[Q-107] is obtained by reacting a compound of Formula [Q-106]:

with an azidation agent followed by a Curtius rearrangement in thepresence of a base and a solvent.
 61. The method of claim 60, whereinthe azidation agent is diphenylphosphoryl azide (DPPA); the base istriethylamine or diisopropylethylamine; the solvent is benzene, toluene,or xylene; and the reacting is carried out at a temperature of from 0°C. to 140° C.
 62. The method of claim 60, wherein the compound ofFormula [Q-106] is obtained by an Ireland Claisen rearrangement reactionof Formula [Q-105]:

by in a solvent, in the presence of a base and a chlorosilane compound,and optionally in the presence of an additive.
 63. The method of claim62, wherein the base is lithium diisopropylamide (LDA), lithiumhexamethyldisilazide (LFMDS), or lithium 2,2,6,6-tetramethylpiperidide(LiTMP); the chlorosilane compound is trimethylsilyl chloride ortert-butyldimethylsilyl chloride; the additive is hexamethylphosphorictriamide (HMPA) or N,N′-dimethylpropyleneurea (DMPU); the solvent isdiethyl ether, 1,2-dimethoxyethane, or tetrahydrofuran; and the IrelandClaisen rearrangement reaction is carried out at a temperature of from−78° C. to 80° C.
 64. The method of claim 62, wherein the compound ofFormula [Q-105] is obtained by reacting a compound of formula [Q-103]:

with a compound of Formula [Q-104]:

in the presence of a condensation agent, a solvent, and optionally anadditive.
 65. The method of claim 64, wherein the condensation agent is1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride,N,N′-dicyclohexylcarbodiimide (DCC), diphenylphosphoryl azide (DPPA), orcarbonyldiimidazole; the additive is 1-hydroxy-1H-benzotriazolemonohydrate (HOBt·H₂O) or 4-dimethylaminopyridine (DMAP); and thesolvent is toluene, dichloromethane, chloroform, tetrahydrofuran,dixoane, N,N-dimethylformamide, dimethylsulfoxide, acetonitrile,acetone, or any mixture of the foregoing; and the reacting is carriedout at a temperature of from 0° C. to 100° C.
 66. A compound selectedfrom the group consisting of:

wherein R¹ is (1) C₄₋₈ alkyl, (2) C₃₋₈ alkyl substituted with onehydroxy, (3) C₄₋₈ alkyl substituted with one halogen, (4) C₄₋₈ alkenyl,(5) C₄₋₈ alkynyl, (6) C₃₋₇ alkyl substituted with one trifluoromethyl,(7) C₁₋₅ alkyl substituted with one substituent selected from GroupX^(a1), (8) C₃₋₆ alkoxy, (9) C₂₋₇ alkoxy substituted with onetrifluoromethyl, (10) C₁₋₃ alkoxy substituted with one substituentselected from Group X^(a2), (11) C₄₋₆ cycloalkyl, (12) C₃₋₆ cycloalkylsubstituted with the same or different one to two C₁₋₅ alkyl, (13) C₅₋₆cycloalkenyl optionally substituted with the same or different one totwo C₁_4 alkyl, (14) spiro C₆₋₁₁ cycloalkyl, (15) C₁₋₃ alkoxycarbonyl,(16) C₃₋₆ alkylsulfanyl, (17) C₃₋₆ alkylsulfinyl, (18) C₃₋₆alkylsulfonyl, (19) C₃₋₆ cycloalkylsulfanyl, (20) C₃₋₆cycloalkylsulfinyl, (21) C₃₋₆ cycloalkylsulfonyl, (22)cyclobutylidenemethyl, (23) cyclopentylidenemethyl, (24)cyclohexylidenemethyl optionally substituted with the same or differentone to two C₁₋₃ alkyl, (25) tetrahydropyran-4-ylidenemethyl, (26) C₃₋₆cycloalkyl substituted with one to the same two halogen, or (27) C₅₋₆cycloalkenyl substituted with one to the same two halogen; Group X^(a1)is (a) C₃₋₆ cycloalkyl optionally substituted with the same or differentone to three C₁₋₅ alkyl, (b) C₃₋₆ cycloalkyl substituted with the sameor different one to two halogen, (c) phenyl, (d) C₂₋₄ alkoxy, (e)trimethylsilyl, (f) carboxy, or (g) tetrahydropyran-4-yl; Group X^(a2)is (a) C₃₋₆ cycloalkyl, (b) phenyl, or (c) C₁₋₄ alkoxy; R² is (1)halogen, (2) C₁₋₆ alkyl, (3) C₁₋₃ alkoxy optionally substituted withphenyl, or (4) trifluoromethyl; n is an integer of 0, 1 or 2, providedthat when n is 2, each R² may be different with each other; or R¹ and R²may combine together with the benzene ring to which they attach to formindanyl where the indanyl may be substituted with the same or differentone to two C₁₋₆ alkyl; R^(3q1) is —Y^(b)—CH₂OP², C₁₋₆ alkyl optionallysubstituted with hydroxy protected with one P², C₃₋₆ cycloalkyloptionally substituted with the same or different one to threesubstituents from Group X^(b), 4-tetrahydropyranyl, or1-methanesulfonyl-3-azetidinyl; Y^(b) is C₁₋₆ alkylene or C₃₋₆cycloalkylene; P² is a protective group selected from the groupconsisting of trimethylsilyl (TMS) and tertbutyldimethylsilyl; GroupX^(b) is halogen or C₁₋₆ alkyl; R⁴ is (1) hydrogen or (2) methyl; R^(5q)is —Y^(c)—COO—R^(q50), hydrogen, C₁₋₄ alkyl optionally substituted withone C₁₋₃ alkoxy or C₃₋₆ cycloalkyl optionally substituted withhydroxy-C₁₋₄ alkyl protected with one P²; R^(q50) is C₁₋₄ alkyl; Y^(c)is C₁₋₆ alkylene optionally substituted with hydroxy protected with oneP², CH₂—CH₂—O—CH₂ or (CH₂)_(m)—Y^(c1)—(CH₂)_(w); m is an integer of 0,1, or 2; w is an integer of 0, 1, or 2; and Y^(c1) is C₃₋₆ cycloalkyleneoptionally substituted with one C₁₋₃ alkyl, phenylene, crosslinked C₅₋₈cycloalkylene, or

 and R⁶ is (1) hydrogen or (2) methyl.
 67. The compound of claim 66,wherein the compound is


68. The compound of claim 66, wherein the compound is